Science.gov

Sample records for post polycythemic myelofibrosis

  1. Morphologic and cytogenetic differences between post-polycythemic myelofibrosis and primary myelofibrosis in fibrotic stage.

    PubMed

    Boiocchi, Leonardo; Mathew, Susan; Gianelli, Umberto; Iurlo, Alessandra; Radice, Tommaso; Barouk-Fox, Sharon; Knowles, Daniel M; Orazi, Attilio

    2013-12-01

    Polycythemia vera and primary myelofibrosis share a propensity to progress toward a myelofibrotic late stage with overlapping clinical characteristics. Bone marrow features potentially useful for distinguishing the two entities have not been thoroughly investigated and, currently, clinical history is used for purposes of disease classification. This study describes in detail the morphologic features of 23 cases of post-polycythemic myelofibrosis and 15 cases of primary myelofibrosis with a similar degree of fibrosis, from two large medical centers. Cytogenetic results were available in 19 post-polycythemic myelofibrosis and in 13 primary myelofibrosis cases. JAK2 status and follow-up information was available in all cases. Cellularity was increased in both groups, but more so in post-polycythemic myelofibrosis than in primary myelofibrosis. In post-polycythemic myelofibrosis, most megakaryocytes retained polycythemia vera-like features including normally folded and/or hyperlobulated nuclei devoid of severe maturation defects; only in a few cases were rare tight clusters present. In primary myelofibrosis cases, megakaryocytes showed pronounced anomalies, including increased nuclear:cytoplasmic ratio, abnormal clumping of chromatin and frequent tight clustering. No differences in blast number (<1%) or in the myeloid:erythroid ratio were observed. Post-polycythemic myelofibrosis showed a higher degree of karyotypic alterations and higher percentage of cases with complex karyotype and/or two or more clones. Chromosome 1 defects were common in post-polycythemic myelofibrosis, whereas isolated del(20q) was the most common alteration in primary myelofibrosis. No survival differences were noted between the two groups. Post-polycythemic myelofibrosis cases retain a distinct megakaryocytic morphology that represents a useful clue for differential diagnosis. In addition, they more often display a complex karyotype than do primary myelofibrosis cases. These results suggest

  2. INC424 for Patients With Myelofibrosis, Post Polycythemia Myelofibrosis or Post-essential Thrombocythemia Myelofibrosis

    ClinicalTrials.gov

    2016-05-24

    Myelofibrosis (PMF); Post Polycythemia Myelofibrosis (PPV MF); Post-essential Thrombocythemia Myelofibrosis (PET-MF); Myelofibrosis; Post Polycythemia Myelofibrosis; Post-essential Thrombocythemia Myelofibrosis

  3. Disruption of the ASXL1 gene is frequent in primary, post-essential thrombocytosis and post-polycythemia vera myelofibrosis, but not essential thrombocytosis or polycythemia vera: analysis of molecular genetics and clinical phenotypes

    PubMed Central

    Stein, Brady L.; Williams, Donna M.; O’Keefe, Christine; Rogers, Ophelia; Ingersoll, Roxann G.; Spivak, Jerry L.; Verma, Amit; Maciejewski, Jarek P.; McDevitt, Michael A.; Moliterno, Alison R.

    2011-01-01

    Background The myeloproliferative neoplasms, essential thrombocytosis, polycythemia vera and primary myelofibrosis, share the same acquired genetic lesion, but the concept of JAK2 V617F serving as the sole lesion responsible for these neoplasms is under question, and there has been interest in identifying additional mutations that may contribute to disease pathogenesis. Because ASXL1 lesions have been increasingly identified in myeloid neoplasms, we examined the relationships of ASXL1 mutation or deletion to both clinical phenotype and associated molecular features in 166 patients with myeloproliferative neoplasms. Design and Methods Exon 12 of ASXL1 was amplified from neutrophil genomic DNA and bidirectionally sequenced in 77 patients with myelofibrosis (including patients with primary and post-essential thrombocytosis or post-polycythemia myelofibrosis), 42 patients with polycythemia vera, 41 with essential thrombocytosis and 6 with post-myelofibrosis acute myeloid leukemia. Pyrosequencing assays were designed to determine the allele percentages of JAK2 V617F (G5073770T), ASXL1 2475dupA, and ASXL1 2846_2847del in neutrophil genomic DNA samples. Clinical and laboratory characteristics of patients with wild-type and ASXL1 mutations were then compared. Results We identified nonsense mutations or hemizygous deletion of ASXL1 in 36% of the patients with myelofibrosis, but very rarely among those with polycythemia vera or essential thrombocytosis. Among the patients with myelofibrosis, those with ASXL1 lesions were not distinguished from their wild-type counterparts with regard to JAK2 V617F status, exposure to chemotherapy or evolution to leukemia. Myelofibrosis patients with ASXL1 lesions were more likely to have received anemia-directed therapy compared to those without lesions [15/26 (58%) versus 11/39 (23%); P=0.02]. Using serial banked samples and quantitative ASXL1 mutant allele burden assays, we observed the acquisition and accumulation of ASXL1 mutations over

  4. A data-driven network model of primary myelofibrosis: transcriptional and post-transcriptional alterations in CD34+ cells.

    PubMed

    Calura, E; Pizzini, S; Bisognin, A; Coppe, A; Sales, G; Gaffo, E; Fanelli, T; Mannarelli, C; Zini, R; Norfo, R; Pennucci, V; Manfredini, R; Romualdi, C; Guglielmelli, P; Vannucchi, A M; Bortoluzzi, S

    2016-01-01

    microRNAs (miRNAs) are relevant in the pathogenesis of primary myelofibrosis (PMF) but our understanding is limited to specific target genes and the overall systemic scenario islacking. By both knowledge-based and ab initio approaches for comparative analysis of CD34+ cells of PMF patients and healthy controls, we identified the deregulated pathways involving miRNAs and genes and new transcriptional and post-transcriptional regulatory circuits in PMF cells. These converge in a unique and integrated cellular process, in which the role of specific miRNAs is to wire, co-regulate and allow a fine crosstalk between the involved processes. The PMF pathway includes Akt signaling, linked to Rho GTPases, CDC42, PLD2, PTEN crosstalk with the hypoxia response and Calcium-linked cellular processes connected to cyclic AMP signaling. Nested on the depicted transcriptional scenario, predicted circuits are reported, opening new hypotheses. Links between miRNAs (miR-106a-5p, miR-20b-5p, miR-20a-5p, miR-17-5p, miR-19b-3p and let-7d-5p) and key transcription factors (MYCN, ATF, CEBPA, REL, IRF and FOXJ2) and their common target genes tantalizingly suggest new path to approach the disease. The study provides a global overview of transcriptional and post-transcriptional deregulations in PMF, and, unifying consolidated and predicted data, could be helpful to identify new combinatorial therapeutic strategy. Interactive PMF network model: http://compgen.bio.unipd.it/pmf-net/. PMID:27341078

  5. Novel therapies for myelofibrosis.

    PubMed

    Stein, Brady L; Cervantes, Francisco; Giles, Francis; Harrison, Claire N; Verstovsek, Srdan

    2015-01-01

    Myelofibrosis (MF), including primary, post-essential thrombocythemia and post-polycythemia vera MF, associates with a reduced quality of life and shortened life expectancy. Dysregulation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway is prominent, even in the absence of the JAK2(V617F) mutation. Therefore, all symptomatic MF patients may potentially derive benefit from JAK inhibitors. Despite the efficacy of JAK inhibitors in controlling signs and symptoms of MF, they do not eradicate the disease. Therefore, JAK inhibitors are currently being tested in combination with other novel therapies, a strategy which may be more effective in reducing disease burden, either by overcoming JAK inhibitor resistance or targeting additional mechanisms of pathogenesis. Additional targets include modulators of epigenetic regulation, pathways that work downstream from JAK/STAT (i.e. mammalian target of rapamycin/AKT/phosphoinositide 3-kinase) heat shock protein 90, hedgehog signaling, pro-fibrotic factors, abnormal megakaryocytes and telomerase. In this review, we discuss novel MF therapeutic strategies. PMID:25860240

  6. Novel Therapies for Myelofibrosis

    PubMed Central

    Stein, Brady L.; Cervantes, Francisco; Giles, Francis; Harrison, Claire N.; Verstovsek, Srdan

    2016-01-01

    Myelofibrosis (MF), including primary, post-essential thrombocythemia and post-polycythemia vera MF, associates with a reduced quality of life and shortened life expectancy. Dysregulation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway is prominent, even in the absence of the JAK2V617F mutation. Therefore, all symptomatic MF patients may potentially derive benefit from JAK inhibitors. Despite the efficacy of JAK inhibitors in controlling signs and symptoms of MF, they do not eradicate the disease. Therefore, JAK inhibitors are currently being tested in combination with other novel therapies, a strategy which may be more effective in reducing disease burden, either by overcoming JAK inhibitor resistance or targeting additional mechanisms of pathogenesis. Additional targets include modulators of epigenetic regulation, pathways that work downstream from JAK/STAT (i.e., mammalian target of rapamycin/AKT/phosphoinositide 3-kinase,) heat shock protein 90, hedgehog signaling, pro-fibrotic factors, abnormal megakaryocytes and telomerase. In this review, we discuss novel MF therapeutic strategies. PMID:25860240

  7. Myelofibrosis and cytopenia are not always malignant.

    PubMed

    Gruson, B; Brevet, M; Vaida, I; Sid idris, S; Damaj, G

    2006-03-01

    Myelofibrosis (MF) is characterized by reticulin fibrosis of the bone marrow. It may occur in neoplastic disorders such as myelofibrosis with myeloid metaplasia (MMM) or other neoplasms involving the bone marrow. However, autoimmune phenomena have been described in patients with MF defining a distinct clinicopathological entity called autoimmune myelofibrosis (AIMF). We report two cases of AIMF and review the literature. PMID:16490694

  8. Brucellosis presenting as myelofibrosis: first case report.

    PubMed

    Bakri, Faris G; Al-Bsoul, Nazzal M; Magableh, Ahmad Y; Shehabi, Asem; Tarawneh, Musleh; Al-Hadidy, Azmy M; Abu-Fara, Mohammed A; Awidi, Abdallah S

    2010-02-01

    We describe the case of a 29-year-old woman who presented with pancytopenia and myelofibrosis. Brucella melitensis was identified in her blood. The patient recovered completely with doxycycline and rifampin. A repeat bone marrow biopsy showed hypercellularity without myelofibrosis. Bone marrow findings in cases of pancytopenia due to brucellosis reveal normocellularity, hypercellularity, hemophagocytosis, or granuloma. To our knowledge this is the first report of brucellosis causing myelofibrosis. Brucellosis should be considered as a possible cause of myelofibrosis in endemic areas. PMID:19501533

  9. Advances in myelofibrosis: a clinical case approach.

    PubMed

    Mascarenhas, John O; Orazi, Attilio; Bhalla, Kapil N; Champlin, Richard E; Harrison, Claire; Hoffman, Ronald

    2013-10-01

    Primary myelofibrosis is a member of the myeloproliferative neoplasms, a diverse group of bone marrow malignancies. Symptoms of myelofibrosis, particularly those associated with splenomegaly (abdominal distention and pain, early satiety, dyspnea, and diarrhea) and constitutional symptoms, represent a substantial burden to patients. Most patients eventually die from the disease, with a median survival ranging from approximately 5-7 years. Mutations in Janus kinase 2 (JAK2), a kinase that is essential for the normal development of erythrocytes, granulocytes, and platelets, notably the V617F mutation, have been identified in approximately 50% of patients with myelofibrosis. The approval of a JAK2 inhibitor in 2011 has improved the outlook of many patients with myelofibrosis and has changed the treatment landscape. This article focuses on some of the important issues in current myelofibrosis treatment management, including differentiation of myelofibrosis from essential thrombocythemia and polycythemia vera, up-dated data on the results of JAK2 inhibitor therapy, the role of epigenetic mechanisms in myelofibrosis pathogenesis, investigational therapies for myelofibrosis, and advances in hematopoietic stem cell transplant. Three myelofibrosis cases are included to underscore the issues in diagnosing and treating this complex disease. PMID:24091929

  10. Imaging findings in patients with myelofibrosis.

    PubMed

    Guermazi, A; de Kerviler, E; Cazals-Hatem, D; Zagdanski, A M; Frija, J

    1999-01-01

    The purpose of this review is to illustrate the wide range of radiological abnormalities in myelofibrosis. Myelofibrosis, also called myeloid metaplasia, is a myeloproliferative disorder of unknown etiology. The common imaging findings in patients with myelofibrosis are osteosclerosis, hepatosplenomegaly, and lymphadenopathies. In addition, extramedullary hematopoiesis may develop in multiple sites such as chest, abdomen, pelvis, and central nervous system, simulating malignant disease. Selected plain-film, CT, and MR images in patients with myelofibrosis are shown as pictorial essay to allow ready recognition of the most common imaging abnormalities of the disease. PMID:10460376

  11. OUTCOME OF TRANSPLANTATION FOR MYELOFIBROSIS

    PubMed Central

    Ballen, Karen K.; Shrestha, Smriti; Sobocinski, Kathleen A; Zhang, Mei-Jie; Bashey, Asad; Bolwell, Brian J.; Cervantes, Francisco; Devine, Steven M.; Gale, Robert Peter; Gupta, Vikas; Hahn, Theresa E.; Hogan, William J.; Kröger, Nicolaus; Litzow, Mark R.; Marks, David I.; Maziarz, Richard T.; McCarthy, Philip L.; Schiller, Gary; Schouten, Harry C.; Roy, Vivek; Wiernik, Peter H.; Horowitz, Mary M.; Giralt, Sergio A.; Arora, Mukta

    2010-01-01

    Myelofibrosis is a myeloproliferative disorder incurable with conventional strategies. Several small series have reported long-term disease free survival after allogeneic hematopoietic cell transplantation. In this study, we analyze the outcomes of 289 patients receiving allogeneic transplantation for primary myelofibrosis between 1989 and 2002, from the database of the Center for International Bone Marrow Transplant Research (CIBMTR). The median age was 47 years (range 18-73 years). Donors were HLA identical siblings in 162 patients, unrelated individuals in 101 patients, and HLA non-identical family members in 26 patients. Patients were treated with a variety of conditioning regimens and graft versus host disease prophylaxis regimens. Splenectomy was performed in 65 patients prior to transplantation. The 100-day transplant related mortality was 18% for HLA identical sibling transplants, 35% for unrelated transplants, and 19% for transplants from alternative related donors. Corresponding 5 year overall survival rates were 37%, 30%, and 40% respectively. Disease-free survival rates were 33%, 27% and 22% respectively. Disease-free survival for patients receiving reduced intensity transplants was comparable, 39% for HLA identical sibling donors and 17% for unrelated donors at three years. In this large retrospective series, allogeneic transplantation for myelofibrosis resulted in long-term relapse-free survival in about one-third of patients. PMID:19879949

  12. Twin troubles--rickets causing myelofibrosis.

    PubMed

    Kamien, Benjamin; Harris, Linda

    2007-01-01

    Myelofibrosis is an uncommon condition that causes anaemia, failure to thrive and massive splenomegaly. This case report describes migrant Sudanese twins who developed myelofibrosis secondary to severe rickets from a combination of poor diet, inadequate sun exposure, and a breastfeeding mother who wore hijab and was also vitamin D deficient. PMID:17635691

  13. Array comparative genomic hybridization and sequencing of 23 genes in 80 patients with myelofibrosis at chronic or acute phase.

    PubMed

    Brecqueville, Mandy; Rey, Jérôme; Devillier, Raynier; Guille, Arnaud; Gillet, Rémi; Adélaide, José; Gelsi-Boyer, Véronique; Arnoulet, Christine; Chaffanet, Max; Mozziconacci, Marie-Joelle; Vey, Norbert; Birnbaum, Daniel; Murati, Anne

    2014-01-01

    Myelofibrosis is a myeloproliferative neoplasm that occurs de novo (primary myelofibrosis) or results from the progression of polycythemia vera or essential thrombocytemia (hereafter designated as secondary myelofibrosis or post-polycythemia vera/ essential thrombocythemia myelofibrosis). To progress in the understanding of myelofibrosis and to find molecular prognostic markers we studied 104 samples of primary and secondary myelofibrosis at chronic (n=68) and acute phases (n=12) from 80 patients, by using array-comparative genomic hybridization and sequencing of 23 genes (ASXL1, BMI1, CBL, DNMT3A, EZH2, IDH1/2, JAK2, K/NRAS, LNK, MPL, NF1, PPP1R16B, PTPN11, RCOR1, SF3B1, SOCS2, SRSF2, SUZ12, TET2, TP53, TRPS1). We found copy number aberrations in 54% of samples, often involving genes with a known or potential role in leukemogenesis. We show that cases carrying a del(20q), del(17) or del(12p) evolve in acute myeloid leukemia (P=0.03). We found that 88% of the cases were mutated, mainly in signaling pathway (JAK2 69%, NF1 6%) and epigenetic genes (ASXL1 26%, TET2 14%, EZH2 8%). Overall survival was poor in patients with more than one mutation (P=0.001) and in patients with JAK2/ASXL1 mutations (P=0.02). Our study highlights the heterogeneity of myelofibrosis, and points to several interesting copy number aberrations and genes with diagnostic and prognostic impact. PMID:23996481

  14. The evolution and clinical relevance of prognostic classification systems in myelofibrosis.

    PubMed

    Bose, Prithviraj; Verstovsek, Srdan

    2016-03-01

    Primary myelofibrosis, the most aggressive of the classic Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), is a clonal disorder characterized by often debilitating constitutional symptoms and splenomegaly, bone marrow fibrosis and resultant cytopenias, extramedullary hematopoiesis, risk of leukemic transformation, and shortened survival. Post-polycythemia vera and post-essential thrombocythemia myelofibrosis represent similar entities, although some differences are being recognized. Attempts to classify patients with myelofibrosis into prognostic categories have been made since the late 1980s, and these scoring systems continue to evolve as new information becomes available. Over the last decade, the molecular pathogenesis of MPNs has been elucidated considerably, and the Janus kinase (JAK) 1/2 inhibitor ruxolitinib is the first drug specifically approved by the US Food and Drug Administration to treat patients with intermediate-risk and high-risk myelofibrosis. This article reviews the evolution of prognostic criteria in myelofibrosis, emphasizing the major systems widely in use today, as well as recently described, novel systems that incorporate emerging data regarding somatic mutations. Risk factors for thrombosis and conversion to MPN blast phase also are discussed. Finally, the practical usefulness of the current prognostic classification systems in terms of clinical decision making is discussed, particularly within the context of some of their inherent weaknesses. Cancer 2016;122:681-692. © 2015 American Cancer Society. PMID:26717494

  15. Fludarabine Phosphate and Total Body Irradiation Followed by a Donor Peripheral Stem Cell Transplant in Treating Patients With Myelodysplastic Syndromes or Myeloproliferative Disorders

    ClinicalTrials.gov

    2016-05-19

    Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Chronic Myelomonocytic Leukemia; de Novo Myelodysplastic Syndrome; Essential Thrombocythemia; Myeloproliferative Neoplasm; Paroxysmal Nocturnal Hemoglobinuria; Polycythemia Vera; Polycythemia Vera, Post-Polycythemic Myelofibrosis Phase; Primary Myelofibrosis; Refractory Anemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Ring Sideroblasts; Refractory Cytopenia With Multilineage Dysplasia; Refractory Cytopenia With Multilineage Dysplasia and Ring Sideroblasts

  16. Recombinant interferon-α in myelofibrosis reduces bone marrow fibrosis, improves its morphology and is associated with clinical response.

    PubMed

    Pizzi, Marco; Silver, Richard T; Barel, Ariella; Orazi, Attilio

    2015-10-01

    Recombinant interferon-α represents a well-established therapeutic option for the treatment of polycythemia vera and essential thrombocythemia. Recent studies also suggest a role for recombinant interferon-α in the treatment of 'early stage' primary myelofibrosis, but few studies have reported the bone marrow changes after clinically successful interferon therapy. The aim of the present study is to detail the histological responses to recombinant interferon-α in primary myelofibrosis and post-polycythemia vera/post-essential thrombocythemia myelofibrosis and to correlate these with clinical findings. We retrospectively studied 12 patients with primary myelofibrosis or post-polycythemia vera/post-essential thrombocythemia myelofibrosis, who had been treated with recombinant interferon-α. Six patients had received other prior cytoreductive therapies. Bone marrow biopsy was assessed for the following histological parameters: (i) cellularity; (ii) myeloid-to-erythroid ratio; (iii) megakaryocyte tight clusters; (iv) megakaryocyte and naked nuclei density; (v) megakaryocytic atypia; (vi) fibrosis; and (vii) the percentage of blasts. Clinical and laboratory data were included: (i) constitutional symptoms; (ii) splenomegaly, if present; and (iii) complete cell blood count. The clinical response to therapy was evaluated using the International Working Group for Myelofibrosis Research and Treatment/European LeukemiaNet response criteria. The Dynamic International Prognostic Scoring System (DIPSS) score was calculated before and after recombinant interferon-α administration. Successful interferon therapy for myelofibrosis was associated with a significant reduction of marrow fibrosis, cellularity, megakaryocyte density and naked nuclei density. The presence of JAK2(V617F) mutation correlated with improved DIPSS score. JAK2(V617F)-negative cases showed worsening of such score or evolution to acute myeloid leukemia. Cytogenetic analysis documented a normal karyotype in all

  17. Myelofibrosis

    MedlinePlus

    ... In young people, bone marrow or stem cell transplantation appears to improve the outlook, and may cure ... is possible for some patients with bone marrow transplantation. Such treatment should be considered for younger patients ...

  18. Therapeutic approaches in myelofibrosis and myelodysplastic/myeloproliferative overlap syndromes.

    PubMed

    Sochacki, Andrew L; Fischer, Melissa A; Savona, Michael R

    2016-01-01

    The discovery of JAK2 (V617F) a decade ago led to optimism for a rapidly developing treatment revolution in Ph(-) myeloproliferative neoplasms. Unlike BCR-ABL, however, JAK2 was found to have a more heterogeneous role in carcinogenesis. Therefore, for years, development of new therapies was slow, despite standard treatment options that did not address the overwhelming symptom burden in patients with primary myelofibrosis (MF), post-essential thrombocythemia MF, post-polycythemia vera MF, and myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) syndromes. JAK-STAT inhibitors have changed this, drastically ameliorating symptoms and ultimately beginning to show evidence of impact on survival. Now, the genetic foundations of myelofibrosis and MDS/MPN are rapidly being elucidated and contributing to targeted therapy development. This has been empowered through updated response criteria for MDS/MPN and refined prognostic scoring systems in these diseases. The aim of this article is to summarize concisely the current and rationally designed investigational therapeutics directed at JAK-STAT, hedgehog, PI3K-Akt, bone marrow fibrosis, telomerase, and rogue epigenetic signaling. The revolution in immunotherapy and novel treatments aimed at previously untargeted signaling pathways provides hope for considerable advancement in therapy options for those with chronic myeloid disease. PMID:27143923

  19. Therapeutic approaches in myelofibrosis and myelodysplastic/myeloproliferative overlap syndromes

    PubMed Central

    Sochacki, Andrew L; Fischer, Melissa A; Savona, Michael R

    2016-01-01

    The discovery of JAK2V617F a decade ago led to optimism for a rapidly developing treatment revolution in Ph− myeloproliferative neoplasms. Unlike BCR–ABL, however, JAK2 was found to have a more heterogeneous role in carcinogenesis. Therefore, for years, development of new therapies was slow, despite standard treatment options that did not address the overwhelming symptom burden in patients with primary myelofibrosis (MF), post-essential thrombocythemia MF, post-polycythemia vera MF, and myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) syndromes. JAK–STAT inhibitors have changed this, drastically ameliorating symptoms and ultimately beginning to show evidence of impact on survival. Now, the genetic foundations of myelofibrosis and MDS/MPN are rapidly being elucidated and contributing to targeted therapy development. This has been empowered through updated response criteria for MDS/MPN and refined prognostic scoring systems in these diseases. The aim of this article is to summarize concisely the current and rationally designed investigational therapeutics directed at JAK–STAT, hedgehog, PI3K–Akt, bone marrow fibrosis, telomerase, and rogue epigenetic signaling. The revolution in immunotherapy and novel treatments aimed at previously untargeted signaling pathways provides hope for considerable advancement in therapy options for those with chronic myeloid disease. PMID:27143923

  20. Efficacy of Ruxolitinib for Myelofibrosis

    PubMed Central

    Santos, Fabio P S; Verstovsek, Srdan

    2016-01-01

    Introduction The discovery of the activating JAK2V617F mutation in patients with myelofibrosis (MF) led to the development of JAK2 inhibitors. The first such inhibitor to enter clinical trials was ruxolitinib. This review summarizes pre-clinical and clinical data of ruxolitinib in MF. Areas covered A literature search through Medline employing the terms “ruxolitinib”, “INCB018424” and “myelofibrosis” was undertaken. The results from phase I/II studies in patients with MF showed that ruxolitinib led to durable improvements in splenomegaly, and symptoms associated with MF. Two phase III trials have compared ruxolitinib against placebo and best available therapy and in both studies ruxolitinib demonstrated superior rates of spleen control and symptom improvement, and additional analysis demonstrated a survival benefit with ruxolitinib treatment. The main toxicities seen with ruxolitinib are cytopenias, which are managed with dose adjustments. Recent reports documented sporadic cases of immunosuppression-related infections. Ruxolitinib is the first drug ever approved for the therapy of patients with MF. Expert Opinion Understanding the factors that predict the rate and duration of response to ruxolitinib would improve our ability to manage patients treated with this medication. Clinical trials combining ruxolitinib with novel compounds that are also active in MF will further improve therapy for this disease. PMID:24856675

  1. Portal hypertension complicating myelofibrosis: reversal following splenectomy.

    PubMed Central

    Lukie, B. E.; Card, R. T.

    1977-01-01

    Portal hypertension occurs in approximately 10% of patients with myelofibrosis. Increased portal blood flow secondary to splenomegaly has been proposed to explain its development. In a 60-year-old woman with proven myelofibrosis of 10 years' duration and gross splenomegaly, portal hypertension developed with esophageal varices and ascites. There was no demonstrable obstruction to portal blood flow. Following splenectomy the ascites and esophageal varices disappeared. Despite the presence of splenic myeloid metaplasia, splenectomy did not impair the patient's hematologic status. Portal hypertension complicating myelofibrosis has a poor prognosis, so careful attention should be given to its detection. Splenectomy may be preferable to portal-systemic shunting in the management of this complication. Images FIG. 1 FIG. 2 PMID:907949

  2. Radioimmunoassay of erythropoietin: circulating levels in normal and polycythemic human beings.

    PubMed

    Garcia, J F; Ebbe, S N; Hollander, L; Cutting, H O; Miller, M E; Cronkite, E P

    1982-05-01

    Techniques are described in detail for the RIA of human Ep in unextracted plasma or serum. With 100 microliters of sample, the essay is sensitive at an Ep concentration of approximately 4 mU/ml, and when required, the sensitivity can be increased to 0.4 mU/ml, a range considerably less than the concentration observed in normal human beings. This is approximately 100 times more sensitive than existing in vivo bioassays for this hormone. Studies concerned with the validation of the Ep RIA show a high degree of correlation with the polycythemic mouse bioassay. Dilutions of a variety of human serum samples show a parallel relationship with the standard reference preparation for Ep. Validation of the RIA is further confirmed by observations of appropriate increases or decreases in circulating Ep levels in physiological and clinical conditions known to be associated with stimulation of suppression of Ep secretion. Significantly different mean serum concentrations of 17.2 mU/ml for normal male subjects and 18.8 mU/ml for normal female subjects were observed. Mean plasma Ep concentrations in patients with polycythemia vera are significantly decreased, and those of patients with secondary polycythemia are significantly increased as compared to plasma levels in normal subjects. These results demonstrate an initial practical value of the Ep RIA inthe hematology clinic, which will most certainly be expanded with its more extensive use. PMID:7069267

  3. Alleviating anemia and thrombocytopenia in myelofibrosis patients.

    PubMed

    Cervantes, Francisco; Correa, Juan-Gonzalo; Hernandez-Boluda, Juan Carlos

    2016-05-01

    Anemia and thrombocytopenia are frequent clinical manifestations of myelofibrosis as well as important prognostic factors of the disease. Concerning the treatment of anemia, the first step should be the correction of reversible contributing factors, such as possible iron, folate and vitamin B12 deficiency. Then, treatment options include erythropoiesis stimulating agents, androgens, immunomodulating drugs, corticosteroids, and splenectomy. Anemia responses may also be observed in some patients treated with JAK inhibitors. However, most patients eventually fail to such therapies and become transfusion dependent. Some of the aforementioned therapies can also improve thrombocytopenia, but the responses are usually observed in patients with moderate platelet count decrease. Allogeneic hematopoietic stem cell transplantation, the only curative treatment of myelofibrosis, can be an alternative for selected patients with cytopenias who are refractory to conventional therapies. However, for the majority of patients, the management of anemia and severe thrombocytopenia remains an unmet need. PMID:26891375

  4. The Dynamic International Prognostic Scoring System for myelofibrosis predicts outcomes after hematopoietic cell transplantation.

    PubMed

    Scott, Bart L; Gooley, Ted A; Sorror, Mohamed L; Rezvani, Andrew R; Linenberger, Michael L; Grim, Jonathan; Sandmaier, Brenda M; Myerson, David; Chauncey, Thomas R; Storb, Rainer; Buxhofer-Ausch, Veronika; Radich, Jerald P; Appelbaum, Frederick R; Deeg, H Joachim

    2012-03-15

    Studies by the International Working Group showed that the prognosis of myelofibrosis patients is predicted by the Dynamic International Prognostic Scoring System (DIPSS) risk categorization, which includes patient age, constitutional symptoms, hemoglobin, leukocyte count, and circulating blasts. We evaluated the prognostic usefulness of the DIPSS in 170 patients with myelofibrosis, 12 to 78 years of age (median, 51.5 years of age), who received hematopoietic cell transplantation (HCT) between 1990 and 2009 from related (n = 86) or unrelated donors (n = 84). By DIPSS, 21 patients had low-risk disease, 48 had intermediate-1, 50 had intermediate-2, and 51 had high-risk disease. Five-year incidence of relapse, relapse-free survival, overall survival, and nonrelapse mortality for all patients were 10%, 57%, 57%, and 34%, respectively. Among patients with DIPSS high-risk disease, the hazard ratio for post-HCT mortality was 4.11 (95% CI, 1.44-11.78; P = .008), and for nonrelapse mortality was 3.41 (95% CI, 1.15-10.09; P = .03) compared with low-risk patients. After a median follow-up of 5.9 years, the median survivals have not been reached for DIPSS risk groups low and intermediate-1, and were 7 and 2.5 years for intermediate-2 and high-risk patients, respectively. Thus, HCT was curative for a large proportion of patients with myelofibrosis, and post-HCT success was dependent on pre-HCT DIPSS classification. PMID:22234678

  5. Ruxolitinib for the treatment of myelofibrosis: a NICE single technology appraisal.

    PubMed

    Wade, Ros; Rose, Micah; Neilson, Aileen Rae; Stirk, Lisa; Rodriguez-Lopez, Rocio; Bowen, David; Craig, Dawn; Woolacott, Nerys

    2013-10-01

    manufacturer's model did not allow for disease progression, did not accurately capture symptomatic relief, had several implausible or unjustified assumptions, and there were several parameter choices that the ERG found sub-optimal. ERG sensitivity analyses found that nearly all plausible adjustments to the model reduced the cost effectiveness of ruxolitinib. It is very likely that the base-case incremental cost-effectiveness ratio of £73,980/quality-adjusted life-year presented by the manufacturer represents a best-case scenario. The NICE Appraisal Committee concluded that ruxolitinib was clinically effective, but could not be considered a cost effective use of National Health Service (NHS) resources for treating disease-related splenomegaly or symptoms in adults with myelofibrosis. Ruxolitinib is not recommended for the treatment of disease-related splenomegaly or symptoms in adult patients with primary myelofibrosis (also known as chronic idiopathic myelofibrosis), post-polycythaemia vera myelofibrosis and post-essential thrombocythaemia myelofibrosis in NICE TA289. PMID:23996108

  6. RUNX1 and NF-E2 upregulation is not specific for MPNs, but is seen in polycythemic disorders with augmented HIF signaling.

    PubMed

    Kapralova, Katarina; Lanikova, Lucie; Lorenzo, Felipe; Song, Jihyun; Horvathova, Monika; Divoky, Vladimir; Prchal, Josef T

    2014-01-16

    Overexpression of transcription factors runt-related transcription factor 1 (RUNX1) and nuclear factor, erythroid-derived 2 (NF-E2) was reported in granulocytes of patients with polycythemia vera and other myeloproliferative neoplasms (MPNs). Further, a transgenic mouse overexpressing the NF-E2 transgene was reported to be a model of MPN. We hypothesized that increased transcripts of RUNX1 and NF-E2 might characterize other polycythemic states with primary polycythemic features, that is, those with exaggerated erythropoiesis due to augmented erythropoietin (EPO) sensitivity. We tested the expression of RUNX1 and NF-E2 in polycythemic patients of diverse phenotypes and molecular causes. We report that RUNX1 and NF-E2 overexpression is not specific for MPN; these transcripts were also significantly elevated in polycythemias with augmented hypoxia-inducible factor activity whose erythroid progenitors were hypersensitive to EPO. RUNX1 and NF-E2 overexpression was not detected in patients with EPO receptor (EPOR) gain-of-function, suggesting distinct mechanisms by which erythroid progenitors in polycythemias with defects of hypoxia sensing and EPOR mutations exert their EPO hypersensitivity. PMID:24297870

  7. Primary autoimmune myelofibrosis: definition of a distinct clinicopathologic syndrome.

    PubMed

    Pullarkat, Vinod; Bass, Randall D; Gong, Jerald Z; Feinstein, Donald I; Brynes, Russell K

    2003-01-01

    Myelofibrosis is characterized by reticulin fibrosis of the bone marrow with resulting features of myelophthisis. Besides hematopoietic malignancies and other neoplasms involving the bone marrow, myelofibrosis has been described in association with autoimmune disorders, especially systemic lupus erythematosus. We describe the clinicopathologic features of a primary form of autoimmune myelofibrosis (AIMF) in patients who do not have systemic lupus erythematosus or another well-defined autoimmune syndrome. Absence of marked splenomegaly, peripheral blood cytopenias with mild teardrop poikilocytosis and leukoerythroblastosis, bone marrow lymphoid aggregates, and presence of autoantibodies are some of the salient features of primary AIMF. AIMF should especially be differentiated from chronic idiopathic myelofibrosis, a neoplastic myeloproliferative disease. Primary AIMF appears to have an excellent prognosis, with all patients reported in this series responding to a short course of corticosteroid therapy. PMID:12508261

  8. Spinal cord compression by extramedullary haematopoiesis in myelofibrosis.

    PubMed Central

    Crawford, D. C.; Nightingale, S.; Bates, D.; Tomlinson, B. E.

    1984-01-01

    A 50-year-old man with a 20-year history of myelofibrosis developed mild impairment of dorsal column sensation and ataxia of gait. A myelogram and subsequent peroperative biopsy demonstrated spinal cord compression due to extramedullary haematopoiesis. There was an excellent clinical response to surgery and radiotherapy. The characteristic clinical features and the pathogenesis of this unusual complication of myelofibrosis and extramedullary haematopoiesis are discussed. Images Fig. 1 PMID:6694952

  9. Bone marrow fibrosis in myelofibrosis: pathogenesis, prognosis and targeted strategies

    PubMed Central

    Zahr, Abdallah Abou; Salama, Mohamed E.; Carreau, Nicole; Tremblay, Douglas; Verstovsek, Srdan; Mesa, Ruben; Hoffman, Ronald; Mascarenhas, John

    2016-01-01

    Bone marrow fibrosis is a central pathological feature and World Health Organization major diagnostic criterion of myelofibrosis. Although bone marrow fibrosis is seen in a variety of malignant and non-malignant disease states, the deposition of reticulin and collagen fibrosis in the bone marrow of patients with myelofibrosis is believed to be mediated by the myelofibrosis hematopoietic stem/progenitor cell, contributing to an impaired microenvironment favoring malignant over normal hematopoiesis. Increased expression of inflammatory cytokines, lysyl oxidase, transforming growth factor-β, impaired megakaryocyte function, and aberrant JAK-STAT signaling have all been implicated in the pathogenesis of bone marrow fibrosis. A number of studies indicate that bone marrow fibrosis is an adverse prognostic variable in myeloproliferative neoplasms. However, modern myelofibrosis prognostication systems utilized in risk-adapted treatment approaches do not include bone marrow fibrosis as a prognostic variable. The specific effect on bone marrow fibrosis of JAK2 inhibition, and other rationally based therapies currently being evaluated in myelofibrosis, has yet to be fully elucidated. Hematopoietic stem cell transplantation remains the only curative therapeutic approach that reliably results in resolution of bone marrow fibrosis in patients with myelofibrosis. Here we review the pathogenesis, biological consequences, and prognostic impact of bone marrow fibrosis. We discuss the rationale of various anti-fibrogenic treatment strategies targeting the clonal hematopoietic stem/progenitor cell, aberrant signaling pathways, fibrogenic cytokines, and the tumor microenvironment. PMID:27252511

  10. Bone marrow fibrosis in myelofibrosis: pathogenesis, prognosis and targeted strategies.

    PubMed

    Zahr, Abdallah Abou; Salama, Mohamed E; Carreau, Nicole; Tremblay, Douglas; Verstovsek, Srdan; Mesa, Ruben; Hoffman, Ronald; Mascarenhas, John

    2016-06-01

    Bone marrow fibrosis is a central pathological feature and World Health Organization major diagnostic criterion of myelofibrosis. Although bone marrow fibrosis is seen in a variety of malignant and non-malignant disease states, the deposition of reticulin and collagen fibrosis in the bone marrow of patients with myelofibrosis is believed to be mediated by the myelofibrosis hematopoietic stem/progenitor cell, contributing to an impaired microenvironment favoring malignant over normal hematopoiesis. Increased expression of inflammatory cytokines, lysyl oxidase, transforming growth factor-β, impaired megakaryocyte function, and aberrant JAK-STAT signaling have all been implicated in the pathogenesis of bone marrow fibrosis. A number of studies indicate that bone marrow fibrosis is an adverse prognostic variable in myeloproliferative neoplasms. However, modern myelofibrosis prognostication systems utilized in risk-adapted treatment approaches do not include bone marrow fibrosis as a prognostic variable. The specific effect on bone marrow fibrosis of JAK2 inhibition, and other rationally based therapies currently being evaluated in myelofibrosis, has yet to be fully elucidated. Hematopoietic stem cell transplantation remains the only curative therapeutic approach that reliably results in resolution of bone marrow fibrosis in patients with myelofibrosis. Here we review the pathogenesis, biological consequences, and prognostic impact of bone marrow fibrosis. We discuss the rationale of various anti-fibrogenic treatment strategies targeting the clonal hematopoietic stem/progenitor cell, aberrant signaling pathways, fibrogenic cytokines, and the tumor microenvironment. PMID:27252511

  11. Acute myelofibrosis in children with Down's syndrome.

    PubMed Central

    Evans, D I

    1975-01-01

    Two boys with Down's syndrome, recognized at birth, developed acute myelogibrosis at the ages of 19 and 21 months. The disorder presented with anaemia and splenomegaly, and clinically resembled acute leukaemia, but bone marrow histology showed a bizarre pattern with generalized fibrosis, markedly increased reticulin, large reticulum cells, and giant cells resembling megakaryocytes. The children survived 6 and 11 months from diagnosis. A third case is quoted (Hillman and Forrester, 1968) which was also studied at this hospital; the features of all 3 cases are similar. There appears to be an increased incidence of acute myelofibrosis in children with Down's syndrome, which may be a further example of the instability of the haemopoietic system in the disease. In children with Down's syndrome and unusual leukaemia-like illness, histological examination of the bone marrow may be diagnostic. Images FIG. 1. FIG. 2. FIG.3. PMID:125073

  12. [Lymphoid myelofibrosis or hairy cell leukemia].

    PubMed

    Lovisetto, P; Pellegrino, P; Tallone, M V; Biarese, V; La Rosa, G F

    1977-05-26

    By lymphoid myelofibrosis or hairy cell leukaemia or tricholeukaemia is meant an unusual haemopathic condition known only for the past few years. It is characterized pathognomonically by the presence of lymphocyte type cells with villous extroflexions, hence the name "hairy cell". Clinically the disease presents as an involutive myelopathy associated with splenomegaly, generally without any particular lymph gland involvement. The attention of students today is concentrated on the nature of the hairy cells; while some are inclined to admit their monocyte or histiocyte derivation, others consider that they derive from B lymphocytes. Therapeutically, almost everybody agrees that splenectomy is the only valid step. A case of H.C.L., which was typical from the clinical and laboratory viewpoints is reported. It is probable that certain haemopathic pictures once classified among atypical leucoses and lymphomas, would today be more correctly classed as hairy cell leukaemia. PMID:327348

  13. Ruxolitinib: An Oral Janus Kinase 1 and Janus Kinase 2 Inhibitor in the Management of Myelofibrosis

    PubMed Central

    Verstovsek, Srdan

    2016-01-01

    Myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET) are referred to as the classic Philadelphia chromosome (BCR-ABL1)-negative myeloproliferative neoplasms. Although each has distinct pathologic features, all 3 display alterations in Janus kinase (JAK) signal transduction activator of transcription signaling. Myelofibrosis is the most serious of the 3, associated with shortened survival (median survival, 5–7 years); bone marrow failure with anemia; progressive splenomegaly; and chronic, burdensome symptoms, including fatigue, night sweats, itching, abdominal discomfort, loss of appetite/early satiety, unintentional weight loss, and bone, chest, and abdominal pain. Treatments for MF have been mainly palliative, with the exception of allogeneic stem cell transplantation, which, although potentially curative, is feasible only in a small subpopulation of patients. In November 2011, ruxolitinib, an inhibitor of JAK1 and JAK2, was approved by the US Food and Drug Administration for the treatment of intermediate- or high-risk MF, including primary MF, post-PV MF, and post-ET MF. In clinical trials, ruxolitinib was shown to reduce spleen volume and improve MF-related symptoms and quality-of-life measures. Evidence also suggests that ruxolitinib therapy has a survival advantage over placebo and best available therapy. Thrombocytopenia and anemia were the most common adverse events with treatment. Ongoing trials are assessing the efficacy and safety of ruxolitinib therapy in patients with PV and ET. PMID:23391678

  14. Sunitinib in Treating Patients With Idiopathic Myelofibrosis

    ClinicalTrials.gov

    2014-05-12

    Accelerated Phase Chronic Myelogenous Leukemia; Acute Undifferentiated Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Blastic Phase Chronic Myelogenous Leukemia; Chronic Myelomonocytic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; Mast Cell Leukemia; Meningeal Chronic Myelogenous Leukemia; Primary Myelofibrosis; Progressive Hairy Cell Leukemia, Initial Treatment; Prolymphocytic Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Stage I Chronic Lymphocytic Leukemia; Stage II Chronic Lymphocytic Leukemia; Stage III Chronic Lymphocytic Leukemia; Stage IV Chronic Lymphocytic Leukemia; T-cell Large Granular Lymphocyte Leukemia; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Adult Acute Myeloid Leukemia; Untreated Hairy Cell Leukemia

  15. Role of neoplastic monocyte-derived fibrocytes in primary myelofibrosis.

    PubMed

    Verstovsek, Srdan; Manshouri, Taghi; Pilling, Darrell; Bueso-Ramos, Carlos E; Newberry, Kate J; Prijic, Sanja; Knez, Liza; Bozinovic, Ksenija; Harris, David M; Spaeth, Erika L; Post, Sean M; Multani, Asha S; Rampal, Raajit K; Ahn, Jihae; Levine, Ross L; Creighton, Chad J; Kantarjian, Hagop M; Estrov, Zeev

    2016-08-22

    Primary myelofibrosis (PMF) is a fatal neoplastic disease characterized by clonal myeloproliferation and progressive bone marrow (BM) fibrosis thought to be induced by mesenchymal stromal cells stimulated by overproduced growth factors. However, tissue fibrosis in other diseases is associated with monocyte-derived fibrocytes. Therefore, we sought to determine whether fibrocytes play a role in the induction of BM fibrosis in PMF. In this study, we show that BM from patients with PMF harbors an abundance of clonal, neoplastic collagen- and fibronectin-producing fibrocytes. Immunodeficient mice transplanted with myelofibrosis patients' BM cells developed a lethal myelofibrosis-like phenotype. Treatment of the xenograft mice with the fibrocyte inhibitor serum amyloid P (SAP; pentraxin-2) significantly prolonged survival and slowed the development of BM fibrosis. Collectively, our data suggest that neoplastic fibrocytes contribute to the induction of BM fibrosis in PMF, and inhibiting fibrocyte differentiation with SAP may interfere with this process. PMID:27481130

  16. Immune Derangements in Patients with Myelofibrosis: The Role of Treg, Th17, and sIL2Rα

    PubMed Central

    Wang, Jen C.; Sindhu, Hemant; Chen, Chi; Kundra, Ajay; Kafeel, Muhammad I.; Wong, Ching; Lichter, Stephen

    2015-01-01

    Myelofibrosis (MF), including primary myelofibrosis, post-essential thrombocythemia MF, and post-polycythemia vera MF, has been reported to be associated with autoimmune phenomena. IMiDs have been reported to be effective in some patients with MF, presumably for their immune-modulator effects. We therefore sought to elucidate the immune derangements in patients with MF. We found no differences in T regulatory cells (Treg) and T helper 17 (Th17) cells in MF patients and normal healthy controls. However, we found significantly elevated soluble interleukin 2 alpha (sIL2Rα) in MF patients compared to those with other myeloproliferative neoplasm diseases and normal healthy controls. Our studies with MF patients further revealed that Treg cells were the predominant cells producing sIL2Rα. sIL2Rα and IL2 complex induced the formation of Treg cells but not the formation of Th1 or Th17 cells. sIL2Rα induced CD8+ T cell proliferation in the presence of Treg cells. Monocytes or neutrophils had no effect on the production of sIL2Rα by Treg cells. Furthermore, we found plasma sIL2Rα levels were correlated to the auto-immune serology in MPN patients and ruxolitinib significantly inhibits the sIL2Rα production by the Treg cells in MF patients which may explain the effects of ruxolitinib on the relief of constitutional symptoms. All these findings suggest that sIL2Rα likely plays a significant role in autoimmune phenomena seen in patients with MF. Further studies of immune derangement may elucidate the mechanism of IMiD, and exploration of immune modulators may prove to be important for treating myelofibrosis. PMID:25793623

  17. Correlation between erythropoietic activity and body growth rate in hypertransfused polycythemic growing rats as the result of an erythropoietin-dependent operating mechanism

    SciTech Connect

    Bozzini, C.E.; Alippi, R.M.; Barcelo, A.C.; Caro, J.

    1989-02-01

    The established relationship between erythropoietic activity and body growth rate in the polycythemic growing rat could be the result of either an erythropoietin (EPO)-dependent or an EPO-independent operating mechanism. The present study was thus undertaken to elucidate the nature of the aforementioned mechanism by assessing the ratio between plasma immunoreactive EPO (iEPO) concentration and erythropoietic activity in young hypertransfused rats for different body growth rates. Red blood cell (RBC)-59Fe uptake was about 75% in 21-day-old rats; it rapidly decreased with time when the animals were placed on a protein-free diet, approaching a level of about 1% by the 10th day of protein starvation. Over the same period plasma iEPO decreased from 55 mU/ml to 7 mU/ml. Body growth rate was 0. Following this ''protein depletion period'' the rats received diets containing different amounts of casein (''protein repletion period'') added isocalorically to the protein-free diet to elicit a rise in body growth rate. Statistically significant relationships (p less than 0.001) were found between dietary casein concentration and body growth rate (r = 0.991), dietary casein concentration and RBC-59Fe uptake (r = 0.991), dietary casein concentration and plasma iEPO level (r = 0.992), body growth rate and RBC-59Fe (r = 0.986), and body growth rate and plasma iEPO level (r = 0.994) in hypertransfused polycythemic rats during the protein repletion period. These findings suggest that the correlation between erythropoietic activity and growth rate in the growing rat is the result of an erythropoietin-dependent operating mechanism, which appears to be independent of the ratio tissue oxygen supply/tissue oxygen demand.

  18. A case of mistaken identity: When lupus masquerades as primary myelofibrosis

    PubMed Central

    Hasrouni, Edy; Rogers, Heesun J; Tabarroki, Ali; Visconte, Valeria; Traina, Fabiola; Afable, Manuel; Sekeres, Mikkael A; Maciejewski, Jaroslaw P

    2013-01-01

    Introduction: Autoimmune myelofibrosis is an uncommon hematologic disease characterized by anemia, bone marrow myelofibrosis, and an autoimmune feature. Myelofibrosis is often associated with other conditions, including infections, nutritional/endocrine dysfunction, toxin/drug exposure, and connective tissue diseases, including scleroderma and systemic lupus erythematosus. Absence of clonal markers (JAK2) and heterogeneity of the symptoms often complicate the diagnosis. Case presentation: Here, we present two cases of systemic lupus erythematosus–induced autoimmune myelofibrosis. The first case is of a 36-year-old African American female with diagnosis of systemic lupus erythematosus at the age of 12 years. The second patient is a 44-year-old African American male with family history of systemic lupus erythematosus who developed anemia and constitutional symptoms later on. Both patients showed hypercellularity and fibrotic changes of the bone marrow. Moreover, mutational analysis showed that both patients were wild type for JAK2 (V617F and exon 12) and MPL (exon 10). Conclusions: These two cases illustrate that anemic patients with fibrotic changes in the bone marrow without other clinicopathologic features associated with primary myelofibrosis in the presence of clinical manifestations and history of an autoimmune disease should suggest an autoimmune myelofibrosis. These cases demonstrate that a good clinical history combined with molecular technologies and pathomorphologic criteria are helpful in distinguishing between primary myelofibrosis and a nonclonal myelofibrosis from an associated condition. PMID:27489629

  19. Tetraspanin CD9 participates in dysmegakaryopoiesis and stromal interactions in primary myelofibrosis

    PubMed Central

    Desterke, Christophe; Martinaud, Christophe; Guerton, Bernadette; Pieri, Lisa; Bogani, Costanza; Clay, Denis; Torossian, Frederic; Lataillade, Jean-Jacques; Hasselbach, Hans C.; Gisslinger, Heinz; Demory, Jean-Loup; Dupriez, Brigitte; Boucheix, Claude; Rubinstein, Eric; Amsellem, Sophie; Vannucchi, Alessandro M.; Le Bousse-Kerdilès, Marie-Caroline

    2015-01-01

    Primary myelofibrosis is characterized by clonal myeloproliferation, dysmegakaryopoiesis, extramedullary hematopoiesis associated with myelofibrosis and altered stroma in the bone marrow and spleen. The expression of CD9, a tetraspanin known to participate in megakaryopoiesis, platelet formation, cell migration and interaction with stroma, is deregulated in patients with primary myelofibrosis and is correlated with stage of myelofibrosis. We investigated whether CD9 participates in the dysmegakaryopoiesis observed in patients and whether it is involved in the altered interplay between megakaryocytes and stromal cells. We found that CD9 expression was modulated during megakaryocyte differentiation in primary myelofibrosis and that cell surface CD9 engagement by antibody ligation improved the dysmegakaryopoiesis by restoring the balance of MAPK and PI3K signaling. When co-cultured on bone marrow mesenchymal stromal cells from patients, megakaryocytes from patients with primary myelofibrosis displayed modified behaviors in terms of adhesion, cell survival and proliferation as compared to megakaryocytes from healthy donors. These modifications were reversed after antibody ligation of cell surface CD9, suggesting the participation of CD9 in the abnormal interplay between primary myelofibrosis megakaryocytes and stroma. Furthermore, silencing of CD9 reduced CXCL12 and CXCR4 expression in primary myelofibrosis megakaryocytes as well as their CXCL12-dependent migration. Collectively, our results indicate that CD9 plays a role in the dysmegakaryopoiesis that occurs in primary myelofibrosis and affects interactions between megakaryocytes and bone marrow stromal cells. These results strengthen the “bad seed in bad soil” hypothesis that we have previously proposed, in which alterations of reciprocal interactions between hematopoietic and stromal cells participate in the pathogenesis of primary myelofibrosis. PMID:25840601

  20. Tetraspanin CD9 participates in dysmegakaryopoiesis and stromal interactions in primary myelofibrosis.

    PubMed

    Desterke, Christophe; Martinaud, Christophe; Guerton, Bernadette; Pieri, Lisa; Bogani, Costanza; Clay, Denis; Torossian, Frederic; Lataillade, Jean-Jacques; Hasselbach, Hans C; Gisslinger, Heinz; Demory, Jean-Loup; Dupriez, Brigitte; Boucheix, Claude; Rubinstein, Eric; Amsellem, Sophie; Vannucchi, Alessandro M; Le Bousse-Kerdilès, Marie-Caroline

    2015-06-01

    Primary myelofibrosis is characterized by clonal myeloproliferation, dysmegakaryopoiesis, extramedullary hematopoiesis associated with myelofibrosis and altered stroma in the bone marrow and spleen. The expression of CD9, a tetraspanin known to participate in megakaryopoiesis, platelet formation, cell migration and interaction with stroma, is deregulated in patients with primary myelofibrosis and is correlated with stage of myelofibrosis. We investigated whether CD9 participates in the dysmegakaryopoiesis observed in patients and whether it is involved in the altered interplay between megakaryocytes and stromal cells. We found that CD9 expression was modulated during megakaryocyte differentiation in primary myelofibrosis and that cell surface CD9 engagement by antibody ligation improved the dysmegakaryopoiesis by restoring the balance of MAPK and PI3K signaling. When co-cultured on bone marrow mesenchymal stromal cells from patients, megakaryocytes from patients with primary myelofibrosis displayed modified behaviors in terms of adhesion, cell survival and proliferation as compared to megakaryocytes from healthy donors. These modifications were reversed after antibody ligation of cell surface CD9, suggesting the participation of CD9 in the abnormal interplay between primary myelofibrosis megakaryocytes and stroma. Furthermore, silencing of CD9 reduced CXCL12 and CXCR4 expression in primary myelofibrosis megakaryocytes as well as their CXCL12-dependent migration. Collectively, our results indicate that CD9 plays a role in the dysmegakaryopoiesis that occurs in primary myelofibrosis and affects interactions between megakaryocytes and bone marrow stromal cells. These results strengthen the "bad seed in bad soil" hypothesis that we have previously proposed, in which alterations of reciprocal interactions between hematopoietic and stromal cells participate in the pathogenesis of primary myelofibrosis. PMID:25840601

  1. Recent advances in understanding myelofibrosis and essential thrombocythemia

    PubMed Central

    Vainchenker, William; Constantinescu, Stefan N.; Plo, Isabelle

    2016-01-01

    The classic BCR-ABL-negative myeloproliferative neoplasms (MPNs), a form of chronic malignant hemopathies, have been classified into polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). ET and PMF are two similar disorders in their pathogenesis, which is marked by a key role of the megakaryocyte (MK) lineage. Whereas ET is characterized by MK proliferation, PMF is also associated with aberrant MK differentiation (myelodysplasia), leading to the release of cytokines in the marrow environment, which causes the development of myelofibrosis. Thus, PMF is associated with both myeloproliferation and different levels of myelodysplastic features. MPNs are mostly driven by mutated genes called MPN drivers, which abnormally activate the cytokine receptor/JAK2 pathway and their downstream effectors. The recent discovery of CALR mutations has closed a gap in our knowledge and has shown that this mutated endoplasmic reticulum chaperone activates the thrombopoietin receptor MPL and JAK2. These genetic studies have shown that there are two main types of MPNs: JAK2V617F-MPNs, including ET, PV, and PMF, and the MPL-/CALR-MPNs, which include only ET and PMF. These MPN driver mutations are associated with additional mutations in genes involved in epigenetics, splicing, and signaling, which can precede or follow the acquisition of MPN driver mutations. They are involved in clonal expansion or phenotypic changes or both, leading to myelofibrosis or leukemic transformation or both. Only a few patients with ET exhibit mutations in non-MPN drivers, whereas the great majority of patients with PMF harbor one or several mutations in these genes. However, the entire pathogenesis of ET and PMF may also depend on other factors, such as the patient’s constitutional genetics, the bone marrow microenvironment, the inflammatory response, and age. Recent advances allowed a better stratification of these diseases and new therapeutic approaches with the

  2. Clinical Significance of Microcytosis in Patients with Primary Myelofibrosis

    PubMed Central

    Strati, Paolo; Pemmaraju, Naveen; Estrov, Zeev; Cardenas-Turanzas, Marylou; Pierce, Sherry; Newberry, Kate J.; Daver, Naval; Cortes, Jorge; Kantarjian, Hagop; Verstovsek, Srdan

    2014-01-01

    Microcytosis is a relatively frequent finding in primary myelofibrosis (PMF); however its prognostic significance is unknown. We identified factors associated with microcytosis in PMF and measured its impact on outcomes. Among 725 patients with PMF, 140 (19%) showed microcytosis. In multivariate analysis, factors associated with microcytosis were absence of prior therapy, low iron, low transferrin saturation (satTF), and splenomegaly. Among 375 untreated patients, low satTF and splenomegaly were associated with microcytosis. Overall, microcytosis was associated with a higher risk of transformation to leukemia (p=0.03), but not shorter leukemia-free survival. Microcytosis in PMF may be related to dysregulation of iron homeostasis. PMID:25217891

  3. Primary myelofibrosis and the "bad seeds in bad soil" concept

    PubMed Central

    2012-01-01

    Primary Myelofibrosis (PMF) is a chronic myeloproliferative neoplasm characterized by a clonal myeloproliferation and a myelofibrosis. The concomitant presence of neoangiogenesis and osteosclerosis suggests a deregulation of medullar stem cell niches in which hematopoietic stem cells are engaged in a constant crosstalk with their stromal environment. Despite the recently discovered mutations including the JAK2Val617F mutation, the primitive molecular event responsible for the clonal hematopoietic proliferation is still unknown. We propose that the "specificity" of the pathological process that caracterizes PMF results from alterations in the cross talk between hematopoietic and stromal cells. These alterations contribute in creating a abnormal microenvironment that participates in the maintenance of the neoplasic clone leading to a misbalance disfavouring normal hematopoiesis; in return or simultaneously, stromal cells constituting the niches are modulated by hematopoietic cells resulting in stroma dysfunctions. Therefore, PMF is a remarkable "model" in which deregulation of the stem cell niche is of utmost importance for the disease development. A better understanding of the crosstalk between stem cells and their niches should imply new therapeutic strategies targeting not only intrinsic defects in stem cells but also regulatory niche-derived signals and, consequently, hematopoietic cell proliferation. PMID:23259918

  4. Treatment and management of myelofibrosis in the era of JAK inhibitors.

    PubMed

    Keohane, Clodagh; Radia, Deepti H; Harrison, Claire N

    2013-01-01

    Myelofibrosis (MF) can present as a primary disorder or evolve from polycythemia vera (PV) or essential thrombocythemia (ET) to post-PV MF or post-ET MF, respectively. MF is characterized by bone marrow fibrosis, splenomegaly, leukoerythroblastosis, extramedullary hematopoiesis, and a collection of debilitating symptoms. Until recently, the therapeutic options for patients with MF consisted of allogeneic hematopoietic stem cell transplant (alloHSCT), the use of cytoreductive agents (ie, hydroxyurea), splenectomy and splenic irradiation for treatment of splenomegaly, and management of anemia with transfusions, erythropoiesis-stimulating agents (ESAs), androgens, and immunomodulatory agents. However, with increased understanding of the pathogenesis of MF resulting from dysregulated Janus kinase (JAK) signaling, new targeted JAK inhibitor therapies, such as ruxolitinib, are now available. The purpose of this article is to review the clinical features of MF, discuss the use and future of JAK inhibitors, reassess when and how to use conventional MF treatments in the context of JAK inhibitors, and provide a perspective on the future of MF treatment. PMID:23990704

  5. Treatment and management of myelofibrosis in the era of JAK inhibitors

    PubMed Central

    Keohane, Clodagh; Radia, Deepti H; Harrison, Claire N

    2013-01-01

    Myelofibrosis (MF) can present as a primary disorder or evolve from polycythemia vera (PV) or essential thrombocythemia (ET) to post-PV MF or post-ET MF, respectively. MF is characterized by bone marrow fibrosis, splenomegaly, leukoerythroblastosis, extramedullary hematopoiesis, and a collection of debilitating symptoms. Until recently, the therapeutic options for patients with MF consisted of allogeneic hematopoietic stem cell transplant (alloHSCT), the use of cytoreductive agents (ie, hydroxyurea), splenectomy and splenic irradiation for treatment of splenomegaly, and management of anemia with transfusions, erythropoiesis-stimulating agents (ESAs), androgens, and immunomodulatory agents. However, with increased understanding of the pathogenesis of MF resulting from dysregulated Janus kinase (JAK) signaling, new targeted JAK inhibitor therapies, such as ruxolitinib, are now available. The purpose of this article is to review the clinical features of MF, discuss the use and future of JAK inhibitors, reassess when and how to use conventional MF treatments in the context of JAK inhibitors, and provide a perspective on the future of MF treatment. PMID:23990704

  6. Safety and efficacy of CYT387, a JAK1 and JAK2 inhibitor, in myelofibrosis

    PubMed Central

    Pardanani, A; Laborde, R R; Lasho, T L; Finke, C; Begna, K; Al-Kali, A; Hogan, W J; Litzow, M R; Leontovich, A; Kowalski, M; Tefferi, A

    2013-01-01

    JAK-STAT is a rational drug target in myelofibrosis (MF) given its association with JAK2/MPL mutations and aberrant inflammatory cytokine expression. We conducted a Phase 1/2 trial of CYT387, a potent JAK1/2 inhibitor, in patients with high- or intermediate-risk primary or post-polycythemia vera/essential thrombocythemia MF. Pre-planned safety and efficacy analysis has been completed for the initial 60 patients. In the dose-escalation phase (n=21), the maximum-tolerated dose was 300 mg/day based on reversible grade 3 headache and asymptomatic hyperlipasemia. Twenty-one and 18 additional patients were accrued at two biologically effective doses, 300 mg/day and 150 mg/day, respectively. Anemia and spleen responses, per International Working Group criteria, were 59% and 48%, respectively. Among 33 patients who were red cell-transfused in the month prior to study entry, 70% achieved a minimum 12-week period without transfusions (range 4.7–>18.3 months). Most patients experienced constitutional symptoms improvement. Grade 3/4 adverse reactions included thrombocytopenia (32%), hyperlipasemia (5%), elevated liver transaminases (3%) and headache (3%). New-onset treatment-related peripheral neuropathy was observed in 22% of patients (sensory symptoms, grade 1). CYT387 is well tolerated and produces significant anemia, spleen and symptom responses in MF patients. Plasma cytokine and gene expression studies suggested a broad anticytokine drug effect. PMID:23459451

  7. One Thousand Patients With Primary Myelofibrosis: The Mayo Clinic Experience

    PubMed Central

    Tefferi, Ayalew; Lasho, Terra L.; Jimma, Thitina; Finke, Christy M.; Gangat, Naseema; Vaidya, Rakhee; Begna, Kebede H.; Al-Kali, Aref; Ketterling, Rhett P.; Hanson, Curtis A.; Pardanani, Animesh

    2012-01-01

    Objective To share our decades of experience with primary myelofibrosis and underscore the importance of outcomes research studies in designing clinical trials and interpreting their results. Patients and Methods One thousand consecutive patients with primary myelofibrosis seen at Mayo Clinic between November 4, 1977, and September 1, 2011, were considered. The International Prognostic Scoring System (IPSS), dynamic IPSS (DIPSS), and DIPSS-plus were applied for risk stratification. Separate analyses were included for patients seen at time of referral (N=1000), at initial diagnosis (N=340), and within or after 1 year of diagnosis (N=660). Results To date, 592 deaths and 68 leukemic transformations have been documented. Parameters at initial diagnosis vs time of referral included median age (66 vs 65 years), male sex (61% vs 62%), red cell transfusion need (24% vs 38%), hemoglobin level less than 10 g/dL (38% vs 54%), platelet count less than 100 × 109/L (18% vs 26%), leukocyte count more than 25 × 109/L (13% vs 16%), marked splenomegaly (21% vs 31%), constitutional symptoms (29% vs 34%), and abnormal karyotype (31% vs 41%). Mutational frequencies were 61% for JAK2V617F, 8% for MPLW515, and 4% for IDH1/2. DIPSS-plus risk distributions at time of referral were 10% low, 15% intermediate-1, 37% intermediate-2, and 37% high. The corresponding median survivals were 17.5, 7.8, 3.6, and 1.8 years vs 20.0, 14.3, 5.3, and 1.7 years for patients younger than 60 years of age. Compared with both DIPSS and IPSS, DIPSS-plus showed better discrimination among risk groups. Five-year leukemic transformation rates were 6% and 21% in low- and high-risk patients, respectively. Conclusion The current document should serve as a valuable resource for patients and physicians and provides context for the design and interpretation of clinical trials. PMID:22212965

  8. Effects of Ruxolitinib Treatment on Metabolic and Nutritional Parameters in Patients With Myelofibrosis From COMFORT-I

    PubMed Central

    Mesa, Ruben A.; Verstovsek, Srdan; Gupta, Vikas; Mascarenhas, John; Atallah, Ehab; Burn, Timothy; Sun, William; Sandor, Victor; Gotlib, Jason

    2015-01-01

    Background In the COMFORT-I study, the Janus kinase (JAK)1/JAK2 inhibitor ruxolitinib provided significant reductions in splenomegaly, improvements in myelofibrosis (MF)-related symptoms, and a survival advantage relative to placebo in patients with intermediate-2 or high-risk MF. This post-hoc analysis assessed the effects of ruxolitinib treatment on measures of metabolic and nutritional status. Patients and Methods Patients were randomized to receive ruxolitinib (n = 155; 15 or 20 mg twice a day for patients with baseline platelet counts of 100–200 × 109/L or > 200 × 109/L, respectively) or placebo (n = 154). The primary endpoint was the proportion of patients with a ≥ 35% spleen volume reduction from baseline to week 24. A secondary endpoint was the proportion of patients with ≥ 50% improvement in Total Symptom Score (TSS) from baseline to week 24, measured by the modified Myelofibrosis Symptom Assessment Form v2.0. Weight, cholesterol, and albumin were measured at specified time points throughout the study. Results Compared with placebo, ruxolitinib treatment was associated with increased weight (mean change: +3.9 kg vs. −1.9 kg), total cholesterol (mean percentage change: +26.4% vs. −3.3%), and albumin levels (mean percentage change: +5.8% vs. −1.7%) at week 24; sustained improvements were observed with longer-term ruxolitinib therapy. Relative to placebo, increases in mean weight, total cholesterol, and albumin levels were observed with ruxolitinib treatment regardless of the degree of spleen volume and TSS reductions at 24 weeks. Conclusion Treatment with ruxolitinib improved measures of metabolic and nutritional status of patients with intermediate-2 or high-risk MF. PMID:25682576

  9. The effect of long-term ruxolitinib treatment on JAK2p.V617F allele burden in patients with myelofibrosis

    PubMed Central

    Radich, Jerald; Burn, Timothy C.; Huber, Reid; Paranagama, Dilan; Verstovsek, Srdan

    2015-01-01

    The JAK2 c.1849G>T (p.V617F) mutation leads to constitutive activation of Janus kinase (JAK)2 and contributes to dysregulated JAK signaling in myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET). In the phase 3 Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment-I trial, patients with MF, post-PV MF, or post-ET MF achieved significant reductions in splenomegaly and improvements in symptoms with ruxolitinib vs placebo at week 24. This long-term follow-up analysis was performed to determine whether ruxolitinib therapy altered the JAK2p.V617F allele burden in JAK2p.V617F-positive patients. Assessments at baseline and weeks 24, 48, 120, 144, 168, and 216 demonstrated reductions in allele burden from baseline with ruxolitinib treatment that correlated with spleen volume reductions. Of 236 JAK2p.V617F-positive patients analyzed, 20 achieved partial and 6 achieved complete molecular responses, with median times to response of 22.2 and 27.5 months, respectively. Allele burden reductions were greater in patients with shorter disease duration, which suggests a potential benefit of earlier treatment. This trial was registered at www.clinicaltrials.gov as #NCT00952289. PMID:26228487

  10. The clinical benefit of ruxolitinib across patient subgroups: analysis of a placebo-controlled, Phase III study in patients with myelofibrosis

    PubMed Central

    Verstovsek, Srdan; Mesa, Ruben A.; Gotlib, Jason; Levy, Richard S.; Gupta, Vikas; DiPersio, John F.; Catalano, John V.; Deininger, Michael; Miller, Carole; Silver, Richard T.; Talpaz, Moshe; Winton, Elliott F.; Harvey, Jimmie H.; Arcasoy, Murat O.; Hexner, Elizabeth; Lyons, Roger M.; Paquette, Ronald; Raza, Azra; Vaddi, Kris; Erickson-Viitanen, Susan; Sun, William; Sandor, Victor; Kantarjian, Hagop M.

    2014-01-01

    Summary Myelofibrosis (MF) patients can present with a wide spectrum of disease characteristics. We analysed the consistency of ruxolitinib efficacy across patient subgroups in the COntrolled MyeloFibrosis Study With ORal JAK Inhibitor Treatment (COMFORT-I,) a double-blind trial, where patients with intermediate-2 or high-risk MF were randomized to twice-daily oral ruxolitinib (n = 155) or placebo (n = 154). Subgroups analysed included MF subtype (primary, post-polycythaemia vera, post-essential thrombocythaemia), age (≤65, > 65 years), International Prognostic Scoring System risk group, baseline Eastern Cooperative Oncology Group performance status (0, 1, ≥2), JAK2 V617F mutation (positive, negative), baseline haemoglobin level (≥100, <100 g/l), baseline platelet count (100–200 × 109/l, >200 × 109/l), baseline palpable spleen size (≤10, >10 cm), and baseline quartile of spleen volume and Total Symptom Score (TSS; Q1 = lowest, Q4 = highest). Mean percentage change from baseline to week 24 in spleen volume and TSS were calculated for ruxolitinib and placebo in each subgroup. Overall survival was estimated by Kaplan–Meier method according to original randomization group. In ruxolitinib-treated patients, reductions in spleen volume and TSS and evidence of improved survival relative to placebo across subgroups were consistent with those seen in the COMFORT-I population, confirming that ruxolitinib is an effective therapy for the spectrum of MF patients studied in COMFORT-I. PMID:23480528

  11. Multiple esophageal variceal ruptures with massive ascites due to myelofibrosis-induced portal hypertension

    PubMed Central

    Tokai, Koichi; Miyatani, Hiroyuki; Yoshida, Yukio; Yamada, Shigeki

    2012-01-01

    A 75-year old man had been diagnosed at 42 years of age as having polycythemia vera and had been monitored at another hospital. Progression of anemia had been recognized at about age 70, and the patient was thus referred to our center in 2008 where secondary myelofibrosis was diagnosed based on bone marrow biopsy findings. Hematemesis due to rupture of esophageal varices occurred in January and February of 2011. The bleeding was stopped by endoscopic variceal ligation. Furthermore, in March of the same year, hematemesis recurred and the patient was transported to our center. He was in irreversible hemorrhagic shock and died. The autopsy showed severe bone marrow fibrosis with mainly argyrophilic fibers, an observation consistent with myelofibrosis. The liver weighed 1856 g the spleen 1572 g, indicating marked hepatosplenomegaly. The liver and spleen both showed extramedullary hemopoiesis. Myelofibrosis is often complicated by portal hypertension and is occasionally associated with gastrointestinal hemorrhage due to esophageal varices. A patient diagnosed as having myelofibrosis needs to be screened for esophageal/gastric varices. Myelofibrosis has a poor prognosis. Therefore, it is necessary to carefully decide the therapeutic strategy in consideration of the patient’s concomitant conditions, treatment invasiveness and quality of life. PMID:22851873

  12. Pivotal contributions of megakaryocytes to the biology of idiopathic myelofibrosis

    PubMed Central

    Ciurea, Stefan O.; Merchant, Delwin; Mahmud, Nadim; Ishii, Takefumi; Zhao, Yan; Hu, Wenyang; Bruno, Edward; Barosi, Giovanni; Xu, Mingjiang

    2007-01-01

    In order to investigate the biologic processes underlying and resulting from the megakaryocytic hyperplasia that characterizes idiopathic myelofibrosis (IMF), peripheral blood CD34+ cells isolated from patients with IMF, polycythemia vera (PV), and G-CSF–mobilized healthy volunteers were cultured in the presence of stem cell factor and thrombopoietin. IMF CD34+ cells generated 24-fold greater numbers of megakaryocytes (MKs) than normal CD34+ cells. IMF MKs were also shown to have a delayed pattern of apoptosis and to overexpress the antiapoptotic protein bcl-xL. MK hyperplasia in IMF is, therefore, likely a consequence of both the increased ability of IMF progenitor cells to generate MKs and a decreased rate of MK apoptosis. Media conditioned (CM) by CD61+ cells generated in vitro from CD34+ cells were then assayed for the levels of growth factors and proteases. Higher levels of transforming growth factor-β (TGF-β) and active matrix metalloproteinase-9 (MMP9) were observed in media conditioned with IMF CD61+ cells than normal or PV CD61+ cells. Both normal and IMF CD61+ cells produced similar levels of VEGF. MK-derived TGF-B and MMP-9, therefore, likely contribute to the development of many pathological epiphenomena associated with IMF. PMID:17473062

  13. Genomic diversity in myeloproliferative neoplasms: focus on myelofibrosis

    PubMed Central

    2015-01-01

    The classical myeloproliferative neoplasms (MPNs) are a group of clonal diseases comprising essential thrombocythaemia (ET), polycythaemia vera (PV) and primary myelofibrosis (PMF). PMF is the rarest disease sub type and has been challenging to address due to the lack of a specific genetic marker, inadequate risk identification models and a highly variable clinical course. Continuous efforts have over time, seen the inclusion of cytogenetic information in prognostic scoring models that have resulted in improved risk stratification models providing further rationale for therapeutic management. Technological advances using single nucleotide polymorphism arrays increased the detection of known and novel MPN related changes and variant detection by massively parallel sequencing provided a large scale screening tool for the multitude of somatic gene mutations that have more recently been described in MPN. Some of these mutations show an association with specific cytogenetic changes or phenotypes. While PMF occurs mainly in adults, it has also been described in paediatric cases and shows distinct histopathological, genetic and clinical features in comparison. This review provides an overview of the genomics landscape of PMF and current developments in MPN therapy. PMID:26835366

  14. Emerging treatment options for myelofibrosis: focus on pacritinib

    PubMed Central

    Chow, Vivian; Weissman, Ashley; O’Connell, Casey Lee; Mehrvar, Azim; Akhtari, Mojtaba

    2016-01-01

    Myelofibrosis (MF) is a myeloid malignancy associated with a heavy symptomatic burden that decreases quality of life and presents a risk for leukemic transformation. While there are limited curative treatments, the recent discovery of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway dysregulation has led to many clinical investigations for new treatment approaches. This review provides practical knowledge on the disease state, an overview of treatment options, and specifically focuses on the efficacy and safety of pacritinib in the management of MF. Pacritinib is a novel selective inhibitor of JAK2 and FMS-related tyrosine kinase 3 (FLT3) currently in Phase III trials for the treatment of MF. Thus far, studies have demonstrated clinical efficacy in reducing splenomegaly and constitutional symptoms. Common adverse events were gastrointestinal in nature, while hematologic toxicity was limited. However, it was announced that all ongoing clinical trials on pacritinib have been placed on hold by the US Food and Drug Administration in February 2016, due to concerns for increased intracranial hemorrhage and cardiac events. With comprehensive risk-benefit analysis of clinical trial data, the utility of pacritinib in the management of MF may be more clearly defined. PMID:27226728

  15. Clinical potential of pacritinib in the treatment of myelofibrosis

    PubMed Central

    Duenas-Perez, Ana B.

    2015-01-01

    Myelofibrosis (MF) is a myeloid disorder caused by a clonal hematopoietic stem-cell proliferation associated with activation of the Janus kinase (JAK) signal transducer and activator of transcription (STAT) signaling pathways. Patients with MF often develop severe splenomegaly, marked symptom burden and significant cytopenias, with a consequent marked negative impact on quality of life and survival. The management of MF patients has dramatically improved with the development of a group of drugs that inhibit JAK signaling. The first of these agents to be approved was ruxolitinib, a JAK1/JAK2 inhibitor, which has been shown to improve both spleen size and symptoms in patients with MF. However, myelotoxicity, particularly of the platelet lineage, significantly limits the patient population who can benefit from this agent. Thus, there is an unmet need for novel agents with limited myelotoxicity to treat MF. Pacritinib, a JAK2 and FMS-like tyrosine kinase 3 (FLT3) inhibitor, has shown promising results in early phase trials with limited myelotoxicity and clinical responses that are comparable with those seen with ruxolitinib, even in patients with severe thrombocytopenia. Currently there are two large phase III clinical trials of pacritinib in MF, including patients with thrombocytopenia, and those previously treated with ruxolitinib. If the encouraging results observed in early phase clinical trials are confirmed, pacritinib will represent a new and exciting treatment option for patients with MF and particularly patients with significant cytopenias. PMID:26288713

  16. Emerging therapeutic options for myelofibrosis: a Canadian perspective

    PubMed Central

    Gupta, Vikas; Foltz, Lynda; Sirhan, Shireen; Busque, Lambert; Turner, A Robert

    2012-01-01

    Myelofibrosis (MF) is a clonal stem cell disorder characterized by cytopenias, splenomegaly, marrow fibrosis, and systemic symptoms due to elevated inflammatory cytokines. MF is associated with decreased survival. The quality of life of patients with MF is similar to other advanced malignancies. Allogeneic hematopoietic cell transplantation is a curative treatment, but is applicable to a minority of patients with MF. None of the conventional therapies are known to alter the natural history of the disease. Significant progress has been made in the last few years in the understanding of disease biology of MF. Discovery of the JAK2V617F mutation paved the way for drug discovery in MF, and the first JAK1/2 inhibitor, ruxolitinib, has been approved by FDA and Health Canada. Several other JAK1/2 inhibitors are at various stages of clinical development. As a consequence, the therapeutic landscape of MF is changing from a disease where no effective therapies existed to one with several novel treatment options on the horizon. In this report, we assess the changing therapeutic options for MF, and critically analyze the position of novel treatments in the current armamentarium. PMID:23119228

  17. Plasma soluble interleukin-2 receptor in patients with primary myelofibrosis.

    PubMed

    Wang, J C; Wang, A

    1994-02-01

    Using en enzyme-linked immunosorbent assay (ELISA) test, the level of soluble Tac peptide, one chain of the human interleukin-2 receptor, was measured in the plasma of 26 patients with primary myelofibrosis (MF), seven patients with polycythaemia vera and 11 normal controls. The plasma soluble interleukin-2 receptor (sIL-2R) was found to be significantly elevated in patients with primary MF compared to polycythaemia vera or controls (P < 0.001), while the plasma sIL-2R of patients with polycythaemia vera also was found to be significantly elevated compared to controls (P < 0.01). The significantly elevated value of sIL-2R seen in primary MF may be secondary to T cell activation resulting from autoimmune phenomena, and myeloblast activation with release of sIL-2R may also be a contributing factor. In primary MF, plasma sIL-2R levels were also found to be correlated to survival, circulating blast cell counts, and thrombocytopenia, but not to white blood cell counts, LDH levels, degree of marrow fibrosis, or degree of splenomegaly. Patients with primary MF with higher titre of plasma sIL-2R had a shorter survival. Further studies involving more patients and longer follow-up may substantiate that plasma sIL-2R is an important prognostic indicator in primary MF. PMID:8199029

  18. Spleens of myelofibrosis patients contain malignant hematopoietic stem cells

    PubMed Central

    Wang, Xiaoli; Prakash, Sonam; Lu, Min; Tripodi, Joseph; Ye, Fei; Najfeld, Vesna; Li, Yan; Schwartz, Myron; Weinberg, Rona; Roda, Paul; Orazi, Attilio; Hoffman, Ronald

    2012-01-01

    Cancer stem cell behavior is thought to be largely determined by intrinsic properties and by regulatory signals provided by the microenvironment. Myelofibrosis (MF) is characterized by hematopoiesis occurring not only in the marrow but also in extramedullary sites such as the spleen. In order to study the effects of these different microenvironments on primitive malignant hematopoietic cells, we phenotypically and functionally characterized splenic and peripheral blood (PB) MF CD34+ cells from patients with MF. MF spleens contained greater numbers of malignant primitive HPCs than PB. Transplantation of PB MF CD34+ cells into immunodeficient (NOD/SCID/IL2Rγnull) mice resulted in a limited degree of donor cell chimerism and a differentiation program skewed toward myeloid lineages. By contrast, transplanted splenic MF CD34+ cells achieved a higher level of chimerism and generated both myeloid and lymphoid cells that contained molecular or cytogenetic abnormalities indicating their malignant nature. Only splenic MF CD34+ cells were able to sustain hematopoiesis for prolonged periods (9 months) and were able to engraft secondary recipients. These data document the existence of MF stem cells (MF-SCs) that reside in the spleens of MF patients and demonstrate that these MF-SCs retain a differentiation program identical to that of normal hematopoietic stem cells. PMID:23023702

  19. Allogeneic Hematopoietic Stem-Cell Transplantation for Myelofibrosis: A Practical Review.

    PubMed

    Farhadfar, Nosha; Cerquozzi, Sonia; Patnaik, Mrinal; Tefferi, Ayalew

    2016-07-01

    Myelofibrosis is a myeloproliferative neoplasm with cardinal features of extramedullary hematopoiesis, hepatosplenomegaly, cytopenias, and constitutional symptoms that result in shortened survival and leukemic transformation. It is a disease predominantly of the elderly, and currently available therapies only offer symptom control without curative benefit or ability to alter disease progression. Allogeneic hematopoietic stem-cell transplant (HSCT) is the only potentially curative intervention; however, this is only feasible in younger and medically fit patients and selectively offered to those with high-risk disease. Despite ongoing advancements, HSCT is associated with substantial morbidity and mortality, and the determination of which patients with myelofibrosis are ideal candidates and the selection of the opportune moment to proceed with transplantation remains challenging. This review summarizes our current recommendations for the role of and indications for HSCT in myelofibrosis. PMID:27407157

  20. Dynamic of bone marrow fibrosis regression predicts survival after allogeneic stem cell transplantation for myelofibrosis.

    PubMed

    Kröger, Nicolaus; Zabelina, Tatjana; Alchalby, Haefaa; Stübig, Thomas; Wolschke, Christine; Ayuk, Francis; von Hünerbein, Natascha; Kvasnicka, Hans-Michael; Thiele, Jürgen; Kreipe, Hans-Heinrich; Büsche, Guntram

    2014-06-01

    We correlate regression of bone marrow fibrosis (BMF) on day 30 and 100 after dose- reduced allogeneic stem cell transplantation (allo-SCT) in 57 patients with primary or post-essential thrombocythemia/polycythemia vera myelofibrosis with graft function and survival. The distribution of International Prognostic Scoring System (IPSS) risk score categories was 1 patient with low risk, 5 patients with intermediate-1 risk, 18 patients with intermediate-2 risk, and 33 patients with high risk. Before allo-SCT, 41 patients (72%) were classified as XXX [myclofibrosis (MF)]-3 and 16 (28%) were classified as MF-2 according to the World Health Organization criteria. At postengraftment day +30 (±10 days), 21% of the patients had near-complete or complete regression of BMF (MF-0/-1), and on day +100 (±20 days), 54% were MF-0/-1. The 5-year overall survival rate at day +100 was 96% in patients with MF-0/-1 and 57% for those with MF-2/-3 (P = .04). There was no difference in BMF regression at day +100 between IPSS high-risk and low/intermediate-risk patients. Complete donor cell chimerism at day +100 was seen in 81% of patients with MF-0/-1 and in 31% of those with MF-2/-3. Patients with MF-2/-3 at day +100 were more likely to be transfusion-dependent for either RBCs (P = .014) or platelets (P = .018). Rapid BMF regression after reduced-intensity conditioning allo-SCT resulted in a favorable survival independent of IPSS risk score at transplantation. PMID:24589549

  1. Prognosis of Primary Myelofibrosis in the Genomic Era.

    PubMed

    Bose, Prithviraj; Verstovsek, Srdan

    2016-08-01

    Currently, prognostication in primary myelofibrosis (PMF) relies on the International Prognostic Scoring System (IPSS), dynamic IPSS (DIPSS), and DIPSS-plus, which incorporate age, blood counts, constitutional symptoms, circulating blasts, red cell transfusion need, and karyotype. Although the JAK2 V617F mutation was discovered a decade ago and MPL mutations shortly thereafter, it was the recent discovery of CALR mutations in the vast majority of JAK2/MPL-unmutated patients and recognition of the powerful impact of CALR mutations and triple-negative (JAK2/MPL/CALR-negative) status on outcome that set the stage for revision of traditional prognostic models to include molecular information. Additionally, the advent of next-generation sequencing has identified a host of previously unrecognized somatic mutations across hematologic malignancies. As in the myelodysplastic syndromes, the majority of common and prognostically informative mutations in PMF affect epigenetic regulation and mRNA splicing. Thus, a need has arisen to incorporate mutational information on genes such as ASXL1 and SRSF2 into risk stratification systems. Mutations in yet other genes appear to be important players in leukemic transformation, and new insights into disease pathogenesis are emerging. Finally, the number of prognostically detrimental mutations may affect both survival and response to ruxolitinib, which has significant implications for clinical decision making. In this review, we briefly summarize the prognostic models in use today and discuss in detail the somatic mutations commonly encountered in patients with PMF, along with their prognostic implications and role in leukemic transformation. Emerging prognostic models that incorporate new molecular information into existing systems or exclude clinical variables are also presented. PMID:27521306

  2. CD133 marks a stem cell population that drives human primary myelofibrosis

    PubMed Central

    Triviai, Ioanna; Stübig, Thomas; Niebuhr, Birte; Hussein, Kais; Tsiftsoglou, Asterios; Fehse, Boris; Stocking, Carol; Kröger, Nicolaus

    2015-01-01

    Primary myelofibrosis is a myeloproliferative neoplasm characterized by bone marrow fibrosis, megakaryocyte atypia, extramedullary hematopoiesis, and transformation to acute myeloid leukemia. To date the stem cell that undergoes the spatial and temporal chain of events during the development of this disease has not been identified. Here we describe a CD133+ stem cell population that drives the pathogenesis of primary myelofibrosis. Patient-derived circulating CD133+ but not CD34+CD133− cells, with a variable burden for JAK2V617F mutation, had multipotent cloning capacity in vitro. CD133+ cells engrafted for up to 10 months in immunocompromised mice and differentiated into JAK2-V617F+ myeloid but not lymphoid progenitors. We observed the persistence of human, atypical JAK2-V617F+ megakaryocytes, the initiation of a prefibrotic state, bone marrow/splenic fibrosis and transition to acute myeloid leukemia. Leukemic cells arose from a subset of CD133+ cells harboring EZH2D265H but lacking a secondary JAK2V617F mutation, consistent with the hypothesis that deregulation of EZH2 activity drives clonal growth and increases the risk of acute myeloid leukemia. This is the first characterization of a patient-derived stem cell population that drives disease resembling both chronic and acute phases of primary myelofibrosis in mice. These results reveal the importance of the CD133 antigen in deciphering the neoplastic clone in primary myelofibrosis and indicate a new therapeutic target for myeloproliferative neoplasms. PMID:25724578

  3. Increased plasma nicotinamide phosphoribosyltransferase is associated with a hyperproliferative phenotype and restrains disease progression in MPN-associated myelofibrosis.

    PubMed

    Rosti, Vittorio; Campanelli, Rita; Massa, Margherita; Viarengo, Gianluca; Villani, Laura; Poletto, Valentina; Bonetti, Elisa; Catarsi, Paolo; Magrini, Umberto; Grolla, Ambra A; Travelli, Cristina; Genazzani, Armando A; Barosi, Giovanni

    2016-07-01

    Myeloproliferative neoplasm (MPN)-associated myelofibrosis is a clonal, neoplastic disorder of the hematopoietic stem cells, in which inflammation and immune dysregulation play an important role. Extracellular nicotinamide phosphoribosyltransferase (eNAMPT), also known as visfatin, is a cytokine implicated in a number of inflammatory and neoplastic diseases. Here plasma levels of eNAMPT in patients with MPN-associated myelofibrosis and their effects on disease phenotype and outcomes were examined. The concordance of eNAMPT levels with the marker of general inflammation high-sensitivity C-reactive protein (hs-CRP) was also studied. A total of 333 MPN-associated myelofibrosis patients (187 males and 146 females) and 31 age- and gender-matched normal-weight healthy subjects were enrolled in the study main body. Levels of eNAMPT and hs-CRP were simultaneously assayed in 209 MPN-associated myelofibrosis patients. Twenty-four polycythemia vera or essential thrombocythemia patients were used as controls. eNAMPT was over expressed in MPN-associated myelofibrosis, and eNAMPT expression was correlated with higher white blood cell count, higher hemoglobin, and higher platelet count, suggesting that eNAMPT is an indispensable permissive agent for myeloproliferation of MPN-associated myelofibrosis. The lack of correlation between eNAMPT and hs-CRP revealed that eNAMPT in MPN-associated myelofibrosis does not behave as a canonical inflammatory cytokine. In addition, higher levels of eNAMPT predicted longer time to blast transformation, and protected against progression toward thrombocytopenia and large splenomegaly. In conclusion, in MPN-associated myelofibrosis high levels of eNAMPT mark the myeloproliferative potential and, at variance with a high number of cancers, are protective against disease progression. Am. J. Hematol. 91:709-713, 2016. © 2016 Wiley Periodicals, Inc. PMID:27074203

  4. Assessment of Liver and Spleen Stiffness in Patients With Myelofibrosis Using FibroScan and Shear Wave Elastography.

    PubMed

    Webb, Muriel; Shibolet, Oren; Halpern, Zamir; Nagar, Meital; Amariglio, Ninette; Levit, Stella; Steinberg, David M; Santo, Erwin; Salomon, Ophira

    2015-09-01

    Liver stiffness and spleen stiffness in patients with myelofibrosis have traditionally been assessed through manual palpation and thus influenced by interobserver variability. In this article, for the first time, liver stiffness and spleen stiffness of patients with myelofibrosis were evaluated through FibroScan and shear wave elastography (SWE). Nine patients with myelofibrosis comprised the study group. They were compared with 11 patients with liver cirrhosis and 8 healthy volunteers. Before the FibroScan study, all patients underwent ultrasound study to delineate the left intercostal space for validated measurements. In patients with myelofibrosis, the mean stiffness of the spleen was 41.3 and 32.9 kilopascals (kPa) through FibroScan and SWE, respectively. The mean stiffness of the liver was 7.8 kPa through FibroScan and 10.4 kPa through SWE. The stiffness of the spleen in patients with cirrhosis was even higher, reaching a mean of 58.5 kPa through FibroScan and 40.5 kPa through SWE. The means were considerably lower among the healthy controls (13.5 and 18.1 kPa, respectively). The correlation between spleen stiffness among the patients with cirrhosis is negative and opposite in direction (r = -0.35) in comparison with the patients with myelofibrosis (r = 0.78). Among the patients with liver cirrhosis and myelofibrosis, spleen size was weakly related to spleen stiffness as assessed through SWE (r = 0.49) but had almost no relation to the FibroScan measure (r = 0.13). The FibroScan and SWE of the spleen have little ability to distinguish between the patients with myelofibrosis and cirrhosis, but they do differentiate both patient groups from the healthy controls. The stiffness of spleen and liver as measured through FibroScan and SWE was not correlated to the longevity of myelofibrosis. PMID:26366688

  5. Dramatic remission of anemia after thymectomy in a patient of idiopathic myelofibrosis with thymoma.

    PubMed

    Shih, Ying-Yih; Hsiao, Liang-Tsai; Yang, Ching-Fen; Wu, Yu-Chung; Chiou, Tzeon-Jye

    2008-01-01

    Anemia is one of the characteristics of idiopathic myelofibrosis (IMF), and malignant thymoma is usually associated with various hematologic disorders, including anemia, pancytopenia, and hypogammaglobulinemia. However, the relationship between IMF and malignant thymoma has not been published before. Here, we report a 48-year-old woman who was initially diagnosed of IMF with severe anemia and transfusion dependent. Five years later, malignant thymoma was found when she was examined for chronic cough. After performing extended thymectomy, her anemia dramatically recovered to normal and sustained for 2 years till last follow-up. Her splenomegaly and myelofibrosis were also improved. We hypothesized that her malignant thymoma induced the progression of IMF, especially in anemia. PMID:18224414

  6. Successful engraftment after reduced-intensity umbilical cord blood transplantation for myelofibrosis.

    PubMed

    Takagi, Shinsuke; Ota, Yasunori; Uchida, Naoyuki; Takahashi, Koichi; Ishiwata, Kazuya; Tsuji, Masanori; Yamamoto, Hisashi; Asano-Mori, Yuki; Matsuno, Naofumi; Masuoka, Kazuhiro; Wake, Atsushi; Miyakoshi, Shigesaburo; Ohashi, Kenichi; Taniguchi, Shuichi

    2010-07-29

    Although allogeneic hematopoietic stem cell transplantation has recently been applied to patients with myelofibrosis with reproducible engraftment and resolution of marrow fibrosis, no data describe the outcomes of umbilical cord blood transplantation. We describe 14 patients with primary (n = 1) and secondary myelofibrosis (n = 13) who underwent reduced-intensity umbilical cord blood transplantation. Conditioning regimens included fludarabine and graft-versus-host disease prophylaxis composed cyclosporine/tacrolimus alone (n = 6) or a combination of tacrolimus and mycophenolate mofetil (n = 8). Thirteen patients achieved neutrophil engraftment at a median of 23 days. The cumulative incidence of neutrophil and platelet engraftment was 92.9% at day 60 and 42.9% at day 100, respectively. Posttransplantation chimerism analysis showed full donor type in all patients at a median of 14 days. The use of umbilical cord blood could be feasible even for patients with severe marrow fibrosis, from the viewpoint of donor cell engraftment. PMID:20439618

  7. Efficacy and Safety of Ruxolitinib in the Treatment of Patients with Myelofibrosis

    PubMed Central

    Yi, Cecilia Arana; Tam, Constantine S.; Verstovsek, Srdan

    2016-01-01

    The JAK 1 and JAK2 inhibitor ruxolitinib has approved indications in myelofibrosis, a BCR-ABL1-negative myeloproliferative neoplasm associated with progressive bone marrow fibrosis and shortened survival. In Phase III clinical studies, ruxolitinib provided rapid and durable improvement of myelofibrosis-related splenomegaly and symptoms irrespective of mutation status, and was associated with a survival advantage compared with placebo or best available therapy. Because of dose-dependent cytopenias, blood count monitoring and dose titration are important to optimize therapy. Specific precautions apply to the treatment of patients with or at risk of serious infections. Discontinuation of ruxolitinib generally leads to symptom return within 1 week. Ruxolitinib also is approved for treatment of patients with polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea. PMID:25757677

  8. Modest Activity of Pomalidomide in Patients with Myelofibrosis and Significant Anemia

    PubMed Central

    Daver, Naval; Shastri, Aditi; Kadia, Tapan; Quintas-Cardama, Alfonso; Jabbour, Elias; Konopleva, Marina; O’Brien, Susan; Pierce, Sherry; Zhou, Lingsha; Cortes, Jorge; Kantarjian, Hagop; Verstovsek, Srdan

    2014-01-01

    We evaluated single agent pomalidomide for myelofibrosis-associated anemia. First, 21 patients received pomalidomide 3.0mg/day on 21-day-on/7-day-off schedule. Due to poor tolerance the study was quickly suspended. Second, 29 patients received pomalidomide 0.5mg/day continuously. Three patients (10%) experienced clinical improvement in hemoglobin per International-Working-Group criteria (median time to response 1.6 months; median response duration 6.7 months). Ten patients were RBC-transfusion-dependent per Delphi criteria; 2 (20%) achieved RBC-transfusion-independence (time to response 0.9 months in both; response duration of 8.3 and 15 months). One grade 3/4 toxicity (neutropenia) occurred. Pomalidomide at low dose is well tolerated but has modest clinical activity in myelofibrosis. PMID:23890523

  9. Bone and bone-marrow blood flow in chronic granulocytic leukemia and primary myelofibrosis

    SciTech Connect

    Lahtinen, R.; Lahtinen, T.; Romppanen, T.

    1982-03-01

    Blood flow in hematopoietic bone marrow and in nonhematopoietic bone has been measured with a Xe-133 washout method in 20 patients with chronic granulocytic leukemia (CGL) and in seven with primary myelofibrosis. Age-matched healthy persons served as controls. Bone-marrow blood flow in CGL was dependent upon the phase of the disease. In the metamorphosis phase, bone-marrow blood flow was high compared with that in the well-controlled phase. Apart from the initial phase, the mean values for bone blood flow in CGL were increased compared with the values of the healthy controls. In myelofibrosis the bone blood flow was also increased. Bone-marrow blood flow in these diseases was dependent upon the cellularity of bone marrow as measured morphometrically.

  10. Ruxolitinib is manageable in patients with myelofibrosis and severe thrombocytopenia: a report on 12 Danish patients.

    PubMed

    Bjørn, Mads Emil; Holmström, Morten Orebo; Hasselbalch, Hans Carl

    2016-01-01

    We report 12 Danish myelofibrosis patients who have been treated successfully with ruxolitinib despite having low platelet counts (< 50 × 10(9)/L) during their treatment-course. The majority of the patients experienced marked clinical improvement. Serious side effects were only recorded in a single patient. It is concluded that JAK-inhibition with ruxolitinib is manageable in patients with low platelet counts and should be considered in symptomatic patients who otherwise might not be candidates for treatment. PMID:25936872

  11. Acute Myeloid Leukemia with Isolated Trisomy 19 Associated with Diffuse Myelofibrosis and Osteosclerosis

    PubMed Central

    Stelling, Adam; Jonas, Brian A.; Rashidi, Hooman H.; Abedi, Mehrdad; Chen, Mingyi

    2015-01-01

    Primary myelofibrosis (PMF), per WHO criteria, is a clonal myeloproliferative neoplasm that usually presents with a proliferation of granulocytic and megakaryocytic lineages with an associated fibrous deposition and extramedullary hematopoiesis. The bone marrow histologic findings of this disorder are typically characterized by the presence of myeloid metaplasia with an associated reactive fibrosis, angiogenesis, and osteosclerosis. However, marked myelofibrosis is not solely confined to PMF and may also be associated with other conditions including but not limited to acute megakaryoblastic leukemias (FAB AML-M7). Here, we describe a rare case of a non-megakaryoblastic acute myeloid leukemia with marked myelofibrosis with osteosclerosis and an isolated trisomy 19. A 19-year-old male presented with severe bone pain of one week duration with a complete blood cell count and peripheral smear showing a mild anemia and occasional circulating blasts. A follow up computed tomography (CT) scan showed diffuse osteosclerosis with no evidence of hepatosplenomegaly or lymphadenopathy. Subsequently, the bone marrow biopsy showed markedly sclerotic bony trabeculae and a hypercellular marrow with marked fibrosis and intervening sheets of immature myeloid cells consistent with myeloblasts with monocytic differentiation. Importantly, these myeloblasts were negative for megakaryocytic markers (CD61 and vWF), erythroid markers (hemoglobin and E-cadherin), and lymphoid markers (CD3, CD19, and TdT). Metaphase cytogenetics showed an isolated triosomy 19 with no JAK2 V617F mutation. The patient was treated with induction chemotherapy followed by allogenic hematopoietic stem cell transplantation which subsequently resulted in a rapid resolution of bone marrow fibrosis, suggesting graft-anti-fibrosis effect. This is a rare case of a non-megakaryoblastic acute myeloid leukemia with myelofibrosis and osteosclerosis with trisomy 19 that may provide insights into the prognosis and therapeutic

  12. The impact of ruxolitinib treatment on inflammation-mediated comorbidities in myelofibrosis and related neoplasms

    PubMed Central

    Bjørn, Mads Emil; Hasselbalch, Hans Carl

    2015-01-01

    Key clinical message The inflammation-mediated comorbidities in myelofibrosis (MF) and related neoplasms (MPNs) likely reflect the concurrent immune deregulation and systemic inflammatory nature of the MPNs, emphasizing the link between chronic systemic inflammation, immune deregulation, and the malignant clone. JAK1-2 inhibitors in MF-patients reduce constitutional symptoms and splenomegaly, but also taget autoimmune and inflammation-mediated comorbidities. PMID:26185657

  13. A Double-Blind Placebo-Controlled Trial of Ruxolitinib for Myelofibrosis

    PubMed Central

    Verstovsek, Srdan; Mesa, Ruben A.; Gotlib, Jason; Levy, Richard S.; Gupta, Vikas; DiPersio, John F.; Catalano, John V.; Deininger, Michael; Miller, Carole; Silver, Richard T.; Talpaz, Moshe; Winton, Elliott F.; Harvey, Jimmie H.; Arcasoy, Murat O.; Hexner, Elizabeth; Lyons, Roger M.; Paquette, Ronald; Raza, Azra; Vaddi, Kris; Erickson-Viitanen, Susan; Koumenis, Iphigenia L.; Sun, William; Sandor, Victor; Kantarjian, Hagop M.

    2016-01-01

    BACKGROUND Ruxolitinib, a selective JAK1 and JAK2 inhibitor, has clinically significant activity in myelofibrosis. METHODS In a double-blind trial, patients with intermediate-2 or high-risk myelofibrosis were randomized to twice-daily oral ruxolitinib (n=155) or placebo (n=154). The primary endpoint was the proportion of patients with ≥35% spleen volume reduction at 24 weeks assessed by magnetic resonance imaging. Secondary endpoints included durability of response, changes in symptom burden (assessed by Total Symptom Score [TSS]), and overall survival. RESULTS In the ruxolitinib group, 41.9% achieved the primary endpoint versus 0.7% in the placebo group (P<0.001). Spleen response was maintained while taking ruxolitinib: 67% of responding patients maintained response for ≥48 weeks. A ≥50% improvement in TSS at 24 weeks was achieved by 45.9% of ruxolitinib-treated versus 5.3% of placebo-treated patients (P<0.001). Thirteen deaths occurred in the ruxolitinib and 24 in the placebo group (hazard ratio, 0.50; 95% CI, 0.25–0.98; P=0.04). Discontinuations for adverse events were similar between groups (11% each). Among ruxolitinib-treated patients, anemia and thrombocytopenia were the most common adverse events, but rarely led to discontinuation (1 patient for each event). Two patients underwent transformation to acute myeloid leukemia (AML), both in the ruxolitinib group. CONCLUSIONS Ruxolitinib provided significant clinical benefits in patients with myelofibrosis by reducing spleen size, improving debilitating myelofibrosis-related symptoms, and improving overall survival. Improvement came at a cost of more frequent anemia and thrombocytopenia in the early part of the treatment period. The imbalance in AML transformation requires attention in further studies. (Funded by Incyte Corporation; ClinicalTrials.gov, NCT00952289) PMID:22375971

  14. Rescue of a primary myelofibrosis model by retinoid-antagonist therapy.

    PubMed

    Hong, Suk-Hyun; Dvorak-Ewell, Melita; Stevens, Hazel Y; Barish, Grant D; Castro, Glenda L; Nofsinger, Russell; Frangos, John A; Shoback, Dolores; Evans, Ronald M

    2013-11-19

    Molecular targeting of the two receptor interaction domains of the epigenetic repressor silencing mediator of retinoid and thyroid hormone receptors (SMRT(mRID)) produced a transplantable skeletal syndrome that reduced radial bone growth, increased numbers of bone-resorbing periosteal osteoclasts, and increased bone fracture risk. Furthermore, SMRT(mRID) mice develop spontaneous primary myelofibrosis, a chronic, usually idiopathic disorder characterized by progressive bone marrow fibrosis. Frequently linked to polycythemia vera and chronic myeloid leukemia, myelofibrosis displays high patient morbidity and mortality, and current treatment is mostly palliative. To decipher the etiology of this disease, we identified the thrombopoietin (Tpo) gene as a target of the SMRT-retinoic acid receptor signaling pathway in bone marrow stromal cells. Chronic induction of Tpo in SMRT(mRID) mice results in up-regulation of TGF-β and PDGF in megakaryocytes, uncontrolled proliferation of bone marrow reticular cells, and fibrosis of the marrow compartment. Of therapeutic relevance, we show that this syndrome can be rescued by retinoid antagonists, demonstrating that the physical interface between SMRT and retinoic acid receptor can be a potential therapeutic target to block primary myelofibrosis disease progression. PMID:24191050

  15. Rescue of a primary myelofibrosis model by retinoid-antagonist therapy

    PubMed Central

    Hong, Suk-Hyun; Dvorak-Ewell, Melita; Stevens, Hazel Y.; Barish, Grant D.; Castro, Glenda L.; Nofsinger, Russell; Frangos, John A.; Shoback, Dolores; Evans, Ronald M.

    2013-01-01

    Molecular targeting of the two receptor interaction domains of the epigenetic repressor silencing mediator of retinoid and thyroid hormone receptors (SMRTmRID) produced a transplantable skeletal syndrome that reduced radial bone growth, increased numbers of bone-resorbing periosteal osteoclasts, and increased bone fracture risk. Furthermore, SMRTmRID mice develop spontaneous primary myelofibrosis, a chronic, usually idiopathic disorder characterized by progressive bone marrow fibrosis. Frequently linked to polycythemia vera and chronic myeloid leukemia, myelofibrosis displays high patient morbidity and mortality, and current treatment is mostly palliative. To decipher the etiology of this disease, we identified the thrombopoietin (Tpo) gene as a target of the SMRT–retinoic acid receptor signaling pathway in bone marrow stromal cells. Chronic induction of Tpo in SMRTmRID mice results in up-regulation of TGF-β and PDGF in megakaryocytes, uncontrolled proliferation of bone marrow reticular cells, and fibrosis of the marrow compartment. Of therapeutic relevance, we show that this syndrome can be rescued by retinoid antagonists, demonstrating that the physical interface between SMRT and retinoic acid receptor can be a potential therapeutic target to block primary myelofibrosis disease progression. PMID:24191050

  16. The Myelofibrosis Symptom Assessment Form (MFSAF): an evidence-based brief inventory to measure quality of life and symptomatic response to treatment in myelofibrosis.

    PubMed

    Mesa, Ruben A; Schwager, Susan; Radia, Deepti; Cheville, Andrea; Hussein, Kebede; Niblack, Joyce; Pardanani, Animesh D; Steensma, David P; Litzow, Mark R; Rivera, Candido E; Camoriano, John; Verstovsek, Srdan; Sloan, Jeffrey; Harrison, Claire; Kantarjian, Hagop; Tefferi, Ayalew

    2009-09-01

    Quality of life (QoL) in patients with myelofibrosis (MF) is severely compromised by severe constitutional symptoms (i.e. fatigue, night sweats, fever, weight loss), pruritus, and symptoms from frequently massive hepatosplenomegaly. Given that no current instrument of patient reported outcomes (PRO) exists that covers the unique spectrum of symptomatology seen in MF patients, we sought to develop a new PRO instrument for MF patients for use in therapeutic clinical trials. Utilizing data from an international Internet-based survey of 458 patients with MF we created a 20-item instrument (MFSAF: Myelofibrosis Symptom Assessment Form) which measures the symptoms reported by >10% of MF patients and includes a measure of QoL. We subsequently validated the MFSAF in a prospective trial of MF patients involving patient and provider feedback, as well as comparison to other validated instruments used in cancer patients. The MFSAF results were highly correlated with other instruments, judged comprehensive and understandable by patients, and should be considered for evaluation of MF symptoms in therapeutic trials. PMID:19250674

  17. Pegylated interferon for the treatment of early myelofibrosis: correlation of serial laboratory studies with response to therapy.

    PubMed

    O'Neill, Caitlin; Siddiqi, Imran; Brynes, Russell K; Vergara-Lluri, Maria; Moschiano, Elizabeth; O'Connell, Casey

    2016-04-01

    Pegylated interferon α-2a (Peg-IFN) has been shown to induce hematologic and molecular responses in patients with the Philadelphia-negative myeloproliferative neoplasms (MPNs), including polycythemia vera (PV) and essential thrombocythemia (ET). We describe a series of patients with long-standing MPNs among whom Peg-IFN was initiated when they developed anemia and increased bone marrow reticulin fibrosis suggestive of early transformation to post-ET (PET) or post-PV (PPV) myelofibrosis (MF). Six patients were treated with Peg-IFN for a mean duration of 33.8 months (range 2-63 months). Five patients had long-standing ET (three were calreticulin (CALR)-positive, one janus kinase 2 (JAK2)-positive, and one JAK2-negative and CALR-negative), and one had long-standing JAK2-positive PV prior to starting Peg-IFN. This is the first study to report that, concurrent with the improvement in anemia, serial laboratory studies demonstrate an increase in serum LDH and left-shifted myeloid cells in the peripheral circulation over approximately 6 months, followed by a gradual normalization of these findings. Splenomegaly also increased and then resolved among responding patients. Serial bone marrow biopsies were available, which showed little change except for improvement in the grade of reticulin fibrosis in two patients. Among patients with early transformation to PET or PPV MF, our data support the efficacy of Peg-IFN in improving hemoglobin levels and reducing splenomegaly. These peripheral blood findings should not, therefore, be considered evidence of treatment failure within the first year of Peg-IFN therapy. PMID:26961933

  18. Depletion of STAT5 blocks TEL–SYK-induced APMF-type leukemia with myelofibrosis and myelodysplasia in mice

    PubMed Central

    Sprissler, C; Belenki, D; Maurer, H; Aumann, K; Pfeifer, D; Klein, C; Müller, T A; Kissel, S; Hülsdünker, J; Alexandrovski, J; Brummer, T; Jumaa, H; Duyster, J; Dierks, C

    2014-01-01

    The spleen tyrosine kinase (SYK) was identified as an oncogenic driver in a broad spectrum of hematologic malignancies. The in vivo comparison of three SYK containing oncogenes, SYKwt, TEL–SYK and IL-2-inducible T-cell kinase (ITK)-SYK revealed a general myeloexpansion and the establishment of three different hematologic (pre)diseases. SYKwt enhanced the myeloid and T-cell compartment, without leukemia/lymphoma development. ITK–SYK caused lethal T-cell lymphomas and the cytoplasmic TEL–SYK fusion induced an acute panmyelosis with myelofibrosis-type acute myeloid leukemia (AML) with up to 50% immature megakaryoblasts infiltrating bone marrow, spleen and liver, additional MPN features (myelofibrosis and granulocyte expansion) and MDS stigmata with megakaryocytic and erythroid dysplasia. LKS cells were reduced and all subsets (LT/ST/MPP) showed reduced proliferation rates. SYK inhibitor treatment (R788) of diseased TEL–SYK mice reduced leukocytosis, spleen and liver infiltration, enhanced the hematocrit and prolonged survival time, but could not significantly reduce myelofibrosis. Stat5 was identified as a major downstream mediator of TEL–SYK in vitro as well as in vivo. Consequently, targeted deletion of Stat5 in vivo completely abrogated TEL–SYK-induced AML and myelofibrosis development, proving Stat5 as a major driver of SYK-induced transformation. Our experiments highlight the important role of SYK in AML and myelofibrosis and prove SYK and STAT5 inhibitors as potent treatment options for those diseases. PMID:25148222

  19. Neutrophilic leukocytosis in advanced stage polycythemia vera: hematopathologic features and prognostic implications.

    PubMed

    Boiocchi, Leonardo; Gianelli, Umberto; Iurlo, Alessandra; Fend, Falko; Bonzheim, Irina; Cattaneo, Daniele; Knowles, Daniel M; Orazi, Attilio

    2015-11-01

    Polycythemia vera in 20-30% of cases progresses towards post-polycythemic myelofibrosis, an advanced phase characterized by decreased red blood cells counts and increasing splenomegaly with extramedullary hematopoiesis. There is evidence that the presence of neutrophilic leukocytosis at polycythemia vera disease outset is associated with an increased risk of recurrent thrombosis. However, its clinical significance when developing later in the course of the disease is not well defined. Over a period of 8 years we identified from the files of two reference centers 10 patients (7M/3F, median age: 68 years) who developed persistent absolute leukocytosis ≥ 13 × 10⁹/l (median: 25.1 × 10⁹/l; range: 16.1-89.7 × 10⁹/l) at or around the time of diagnosis of post-polycythemic myelofibrosis (median interval from diagnosis:0 months; range: -6/31) and persisted for a median period of 13 months. Peripheral blood smears showed numerous neutrophils without dysplastic features and, in four, ≥ 10% immature myeloid precursors. In five cases, corresponding marrow specimens obtained at or immediately after the onset of leukocytosis showed a markedly increased myeloid:erythroid ratio due to granulocytic proliferation. No change in JAK2 and BCR-ABL1 status or cytogenetic evolution was associated with the development of leukocytosis. The mutational status of CSF3R, SETBP1, and SRSF2, genes associated with other chronic myeloid neoplasms where neutrophilic leukocytosis occurs, was investigated but all cases showed wild-type only alleles. Four patients died after developing leukocytosis and one experienced worsening disease. Compared with a control group of post-polycythemic myelofibrosis patients (n=23) who never developed persistent leukocytosis, patients with leukocytosis showed higher white blood cells counts and a shorter overall survival. This is the first study describing the development of significant neutrophilic leukocytosis during advanced stages of polycythemia vera

  20. Reversible bone marrow aplasia induced by pegylated interferon-α-2a therapy in a patient with primary myelofibrosis.

    PubMed

    Mainali, Naba R; Bhatt, Vijaya R; Kedia, Shiksha; Krishnamurthy, Jairam; Wake, Laura M; Akhtari, Mojtaba

    2014-10-01

    Interferon has been widely used in the management of patients with hematological malignancies such as polycythemia vera, myelofibrosis, chronic myeloid leukemia and viral infections such as chronic hepatitis C. Hematological adverse effects such as cytopenias have been observed, particularly in patients who receive a combination of interferon-α-2a and ribavirin for hepatitis C. Mild myelosuppression can be seen with pegylated interferon; however, bone marrow aplasia in patients with myelofibrosis has not been reported. It is important to be aware of such a serious complication since persistent bone marrow aplasia can be fatal. We describe a case of pegylated interferon-induced reversible bone marrow aplasia in a patient with primary myelofibrosis. PMID:24067929

  1. Safety and Efficacy of TG101348, a Selective JAK2 Inhibitor, in Myelofibrosis

    PubMed Central

    Pardanani, Animesh; Gotlib, Jason R.; Jamieson, Catriona; Cortes, Jorge E.; Talpaz, Moshe; Stone, Richard M.; Silverman, Michael H.; Gilliland, D. Gary; Shorr, Jolene; Tefferi, Ayalew

    2011-01-01

    Purpose Myelofibrosis is a myeloid malignancy associated with anemia, splenomegaly, and constitutional symptoms. Patients frequently harbor JAK-STAT activating mutations that are sensitive to TG101348, a selective small-molecule Janus kinase 2 (JAK2) inhibitor. Patients and Methods In a multicenter phase I trial, oral TG101348 was administered once a day to patients with high- or intermediate-risk primary or post–polycythemia vera/essential thrombocythemia myelofibrosis. Results Fifty-nine patients were treated, including 28 in the dose-escalation phase. The maximum-tolerated dose was 680 mg/d, and dose-limiting toxicity was a reversible and asymptomatic increase in the serum amylase level. Forty-three patients (73%) continued treatment beyond six cycles; the median cumulative exposure to TG101348 was 380 days. Adverse events included nausea, vomiting, diarrhea, anemia, and thrombocytopenia; corresponding grades 3 to 4 incidence rates were 3%, 3%, 10%, 35%, and 24%. TG101348 treatment had modest effect on serum cytokine levels, but greater than half of the patients with early satiety, night sweats, fatigue, pruritus, and cough achieved rapid and durable improvement in these symptoms. By six and 12 cycles of treatment, 39% and 47% of patients, respectively, had achieved a spleen response per International Working Group criteria. The majority of patients with leukocytosis or thrombocytosis at baseline (n = 28 and n = 10, respectively) achieved normalization of blood counts after six (57% and 90%, respectively) and 12 (56% and 88%, respectively) cycles. A significant decrease in JAK2 V617F allele burden was observed at 6 months in mutation-positive patients (n = 51; P = .04), particularly in the subgroup with allele burden greater than 20% (n = 23; P < .01); the decrease was durable at 12 months. Conclusion TG101348 is well tolerated and produces significant reduction in disease burden and durable clinical benefit in patients with myelofibrosis. PMID:21220608

  2. Outcome after Transplantation According to Reduced-Intensity Conditioning Regimen in Patients Undergoing Transplantation for Myelofibrosis.

    PubMed

    Robin, Marie; Porcher, Raphael; Wolschke, Christine; Sicre de Fontbrune, Flore; Alchalby, Haefaa; Christopeit, Maximilian; Cassinat, Bruno; Zabelina, Tatjana; Peffault de Latour, Régis; Ayuk, Francis; Socié, Gérard; Kröger, Nicolaus

    2016-07-01

    Allogeneic hematopoietic stem cell transplantation remains the sole curative option for myelofibrosis. Many transplantation recipients receive a reduced-intensity conditioning (RIC) regimen owing to age or comorbidities; however, there is little published evidence to guide the choice of RIC regimen. In this study, we compared outcomes in patients who received 1 of 2 frequently used RIC regimens for patients with myelofibrosis: fludarabine-busulfan (FB) and fludarabine-melphalan (FM). A total of 160 patients underwent a RIC allograft procedure (FB group, n = 105; FM group, n = 55). We have developed a complex statistical model involving weighting and adjustment to permit comparison between these 2 groups. After weighting, the incidence of acute graft-versus-host disease (GVHD) was 62% in the FM group and 31% in the FB group (P = .001), and the corresponding incidence of chronic GVHD was 49% and 53%, respectively. The 7-year progression-free survival was were 52% in the FM group versus 33% in the FB group, and the 7-year overall survival rate 52% in the FM group versus 59% in the FB group. Nonrelapse mortality (NRM) was 43% in the FM group and 31% in the FB group. Multivariable analyses revealed no significant differences in PFS between the 2 groups; however, the relapse rate was significantly lower in the FM group (hazard ratio, 9.21; P = .008), whereas a trend toward reduced NRM was seen in the FB group (hazard ratio, 0.51; P = .068). In conclusion, both regimens appear to be efficient in mediating disease control and can be used to successfully condition patients with myelofibrosis. The FM regimen appears to induce more NRM than the FB regimen, but with augmented control of disease, leading to comparable overall survival rates for both regimens. PMID:26970380

  3. Pomalidomide Is Active in the Treatment of Anemia Associated With Myelofibrosis

    PubMed Central

    Tefferi, Ayalew; Verstovsek, Srdan; Barosi, Giovanni; Passamonti, Francesco; Roboz, Gail J.; Gisslinger, Heinz; Paquette, Ronald L.; Cervantes, Francisco; Rivera, Candido E.; Deeg, H. Joachim; Thiele, Juergen; Kvasnicka, Hans M.; Vardiman, James W.; Zhang, Yanming; Bekele, B. Nebiyou; Mesa, Ruben A.; Gale, Robert P.; Kantarjian, Hagop M.

    2009-01-01

    Purpose Thalidomide and lenalidomide can alleviate anemia in myelofibrosis. However, their value is undermined by their respective potential to cause peripheral neuropathy and myelosuppression. We therefore evaluated the safety and therapeutic activity of another immunomodulatory drug, pomalidomide. Methods In a phase II randomized, multicenter, double-blind, adaptive design study, four treatment arms were evaluated: pomalidomide (2 mg/d) plus placebo, pomalidomide (2 mg/d) plus prednisone, pomalidomide (0.5 mg/d) plus prednisone, and prednisone plus placebo. Pomalidomide was administered for up to 12 28-day treatment cycles. Prednisone (30 mg/d) was given in a tapering dose schedule during the first three cycles. Response was assessed by International Working Group criteria. Results Eighty-four patients with myelofibrosis-associated anemia were randomly assigned to the aforementioned treatment arms: 22, 19, 22, and 21, respectively. Response in anemia was documented in 20 patients, including 15 who became transfusion independent. Response rates in the four treatment arms were 23% (95% CI, 5% to 41%), 16% (95% CI, 0% to 33%), 36% (95% CI, 16% to 56%), and 19% (95% CI, 2% to 36%). The corresponding figures for patients receiving ≥ 3 cycles of treatment (n = 62) were 38%, 23%, 40%, and 25%. Response to pomalidomide with or without prednisone was durable (range, 3.2 to 16.9+ months) and significantly better in the absence of leukocytosis (37% v 8%; P = .01); JAK2V617F or cytogenetic status did not affect response. Grade ≥ 3 toxicities were infrequent and included (in each treatment arm) neutropenia (9%; 16%; 5%; 5%), thrombocytopenia (14%; 16%; 9%; 5%), and thrombosis (9%; 5%; 0%; 0%). Conclusion Pomalidomide therapy at 0.5 or 2 mg/d with or without an abbreviated course of prednisone is well tolerated in patients with myelofibrosis and active in the treatment of anemia. PMID:19652059

  4. Ferrokinetic study of splenic erythropoiesis: Relationships among clinical diagnosis, myelofibrosis, splenomegaly, and extramedullary erythropoiesis

    SciTech Connect

    Beguin, Y.; Fillet, G.; Bury, J.; Fairon, Y. )

    1989-10-01

    Splenic erythropoiesis was demonstrated by surface counting of {sup 59}Fe in 129 of 1,350 ferrokinetic studies performed over a 15 year period. These 129 studies were carried out in 108 patients, including 40 with chronic myelogenous leukemia (CML), 24 with agnogenic myeloid metaplasia (AMM), 18 with polycythemia vera (PV), six with a myelodysplastic syndrome, five with acute leukemia, three with prostate or breast carcinoma, two each with aplastic anemia or Hodgkin's disease, and one each with idiopathic thrombocythemia, multiple myeloma, chronic renal failure, or treated hypopituitarism. Splenomegaly was present in 83% of the studies and hepatomegaly in 72%. Grade II-III myelofibrosis was demonstrated in 62% of the cases. Hepatic erythropoiesis was present in 77% of the studies (only 38% in PV), and marrow erythropoiesis was undetectable in 33%. Total erythropoiesis was about twice normal (range 0.2 to 8 times normal) but was ineffective to varying degrees in 86% of the studies. Relationships between organomegaly, myelofibrosis, and extramedullary erythropoiesis, as well as differences among clinical disorders, are discussed. Differences observed between CML in chronic or blastic phase suggested that the erythroid cell line was involved in the proliferative process. It is concluded that splenic erythropoiesis (1) is encountered in a variety of clinical conditions; (2) is not necessarily associated with splenomegaly or myelofibrosis, even in the myeloproliferative disorders; (3) is part of a predominantly extramedullary (in the liver as well as in the spleen), expanded, and largely inefficient total erythropoiesis; and (4) can be evaluated in a semiquantitative manner by surface counting.

  5. Arthritis due to synovial involvement by extramedullary haematopoiesis in myelofibrosis with myeloid metaplasia.

    PubMed Central

    Heinicke, M H; Zarrabi, M H; Gorevic, P D

    1983-01-01

    A 60-year-old man presented with polyarthralgias, a psoriasiform rash, and severe elbow pain. Peripheral blood smear and bone marrow biopsy established a diagnosis of myelofibrosis with myeloid metaplasia. Biopsy of the skin lesions revealed a nonspecific dermatitis. The clinical presentation was inconsistent with psoriatic arthritis, and there was no evidence for associated gout or collagen-vascular disease. Histological examination of tissue taken at the time of synovectomy indicated elbow arthritis to be due to myeloid metaplasia involving the synovial membrane. Images PMID:6847265

  6. Discrepancy in Diagnosis of Primary Myelofibrosis between Referral and Tertiary Care Centers

    PubMed Central

    Yi, Cecilia Arana; Jeyakumar, Ghayathri; Medina, Pedro; Cortes, Jorge; Pierce, Sherry; Bueso-Ramos, Carlos; Kantarjian, Hagop; Verstovsek, Srdan

    2015-01-01

    Primary myelofibrosis (PMF) is myeloproliferative neoplasm whose diagnosis is based on a combination of clinical and pathology criteria. We evaluated 560 consecutive patients who were diagnosed with PMF upon a referral to our center and evaluated the frequency of and reasons for diagnostic discordance. Discordance in the diagnosis was found in 70 (12.5%) patients. Discordant cases had a significantly lower grade of bone marrow fibrosis (grade 0–1), more likely to be JAK2V617F-mutation negative, and have no peripheral blood blasts, possibly explaining the difficulty in making a proper diagnosis and underscoring the need for a complete evaluation at a tertiary center. PMID:24284333

  7. Omental sclerosing extramedullary hematopoietic tumors in Janus kinase-2 negative myelofibrosis: caveat at frozen section.

    PubMed

    Shinde, Sweety V; Shenoy, Asha S; Balsarkar, Dharmesh J; Shah, Vinaya B

    2014-01-01

    Sclerosing extramedullary hematopoietic tumors (SEMHTs) are associated with chronic myeloproliferative neoplasms. These extremely rare mass lesions were first described in kidney and peritoneum. On histopathology, they are characterized by sclerosis, entrapped fat, atypical megakaryocytes with myeloid and erythroid elements. Only approximately ten cases have been subsequently reported in orbit, lacrimal system, liver, omentum, and skin. The authors present a case of SEMHTs as incidentally detected omental nodules, while the patient was undergoing splenectomy for Janus kinase-2 negative myelofibrosis. The authors postulate their origin in omentum-associated lymphoid tissue; and highlight the diagnostic dilemma presented by SEMHTs at frozen section. PMID:25118752

  8. Development of myelofibrosis during eltrombopag treatment in a patient with immune thrombocytopenia.

    PubMed

    Horikoshi, Akira; Tsukuda, Jumpei; Abe, Ryouhei; Fujiwara, Naoki; Ito, Eisaku; Takaku, Tomoo

    2016-05-01

    Eltrombopag, a thrombopoietin (TPO) receptor agonist, is effective for treating refractory immune thrombocytopenia (ITP). However, the development of bone marrow fibrosis is a concern. A 78-year-old man was diagnosed with ITP in 2004. His platelet count did not increase after eltrombopag treatment initiation in 2014. However, anemia progressed, along with the presence of immature myelocytes, erythroblasts, and tear drop cells. At 8 months after initiating eltrombopag treatment, the patient underwent a bone marrow biopsy that showed grade 2 myelofibrosis. Hence, eltrombopag was discontinued. In our experience with this case indicates that careful observation is required while using TPO receptor agonists. PMID:27263792

  9. European Bone Marrow Working Group trial on reproducibility of World Health Organization criteria to discriminate essential thrombocythemia from prefibrotic primary myelofibrosis

    PubMed Central

    Buhr, Thomas; Hebeda, Konnie; Kaloutsi, Vassiliki; Porwit, Anna; Van der Walt, Jon; Kreipe, Hans

    2012-01-01

    Background The World Health Organization classification of myeloproliferative neoplasms discriminates between essential thrombocythemia and the prefibrotic phase of primary myelofibrosis. This discrimination is clinically relevant because essential thrombocythemia is associated with a favorable prognosis whereas patients with primary myelofibrosis have a higher risk of progression to myelofibrosis or blast crisis. Design and Methods To assess the reproducibility of the classification, six hematopathologists from five European countries re-classified 102 non-fibrotic bone marrow trephines, obtained because of sustained thrombocytosis. Results Consensus on histological classification defined as at least four identical diagnoses occurred for 63% of the samples. Inter-observer agreement showed low to moderate kappa values (0.28 to 0.57, average 0.41). The percentage of unclassifiable myeloproliferative neoplasms rose from 2% to 23% when minor criteria for primary myelofibrosis were taken into account. In contrast, the frequency of primary myelofibrosis dropped from 23% to 7%, indicating that the majority of patients with a histological diagnosis of primary myelofibrosis did not fulfill the complete criteria for this disease. Thus, over 50% of cases in this series either could not be reproducibly classified or fell into the category of unclassifiable myeloproliferative neoplasms. Conclusions World Health Organization criteria for discrimination of essential thrombocythemia from prefibrotic primary myelofibrosis are poorly to only moderately reproducible and lead to a higher proportion of non-classifiable myeloproliferative neoplasms than histology alone. PMID:22058215

  10. Bone marrow fibrosis in primary myelofibrosis: pathogenic mechanisms and the role of TGF-β

    PubMed Central

    Agarwal, Archana; Morrone, Kerry; Bartenstein, Matthias; Zhao, Zhizhuang Joe

    2016-01-01

    Primary myelofibrosis (PMF) is a Philadelphia chromosome negative myeloproliferative neoplasm (MPN) with adverse prognosis and is associated with bone marrow fibrosis and extramedullary hematopoiesis. Even though the discovery of the Janus kinase 2 (JAK2), thrombopoietin receptor (MPL) and calreticulin (CALR) mutations have brought new insights into the complex pathogenesis of MPNs, the etiology of fibrosis is not well understood. Furthermore, since JAK2 inhibitors do not lead to reversal of fibrosis further understanding of the biology of fibrotic process is needed for future therapeutic discovery. Transforming growth factor beta (TGF-β) is implicated as an important cytokine in pathogenesis of bone marrow fibrosis. Various mouse models have been developed and have established the role of TGF-β in the pathogenesis of fibrosis. Understanding the molecular alterations that lead to TGF-β mediated effects on bone marrow microenvironment can uncover newer therapeutic targets against myelofibrosis. Inhibition of the TGF-β pathway in conjunction with other therapies might prove useful in the reversal of bone marrow fibrosis in PMF. PMID:27358897

  11. The ultrastructure of radiation-induced endosteal myelofibrosis in the dog

    SciTech Connect

    Seed, T.M.; Chubb, G.T.; Tolle, D.V.; Fritz, T.F.; Poole, C.M.; Doyle, D.E.; Lombard, L.S.; Kaspar, L.V.

    1982-01-01

    A rapidly developing, progressive form of endosteal myelofibrosis (MF) (with myeloid meta-plasia) has been shown to occur at low frequency (approx. 4%) in dogs exposed continuously to low daily doses (10 R/day) of whole-body gamma irradiation. We report in this study the morphological details of the endosteal surface during both preclinical and clinical phases of developing MF by combination light microscopy and scanning/transmission electron microscopy. Pronounced alterations of the endosteum were observed and included:(1) during the early preclinical phases, a progressive time-dependent transition of the endosteal surface from predominantly resting to actively formative and resorptive states; and (2) during the late preclinical phase, aberrant autonomous osteogenic process(es) characterized by a marked reduction in the resorptive, osteoclast-associated endosteal areas occuring concomitantly with further increases in formative areas of the endosteum. Localized patches of overlapping, morphologically transformed endosteal cells (i.e., round-osteoblastic to branched-reticular shaped) were observed within the morphologically reactive, formative endosteum. Osteogenic-endosteal change coincided with major restructuring of the hematopoietic parenchyma and supporting stromal network. We discuss the possibility that the early occurring endosteal changes are causally linked to normal reparative functions that operate during regenerative hematopoiesis following local and systemic injury. Based on morphological data collected during the late preclinical phase, we speculate that the mechanism of myelofibrosis induction involves the failure to terminate early osteogenic-dependent repair sequences.

  12. Inflammation as a Keystone of Bone Marrow Stroma Alterations in Primary Myelofibrosis

    PubMed Central

    Desterke, Christophe; Martinaud, Christophe; Ruzehaji, Nadira; Le Bousse-Kerdilès, Marie-Caroline

    2015-01-01

    Primary myelofibrosis (PMF) is a clonal myeloproliferative neoplasm where severity as well as treatment complexity is mainly attributed to a long lasting disease and presence of bone marrow stroma alterations as evidenced by myelofibrosis, neoangiogenesis, and osteosclerosis. While recent understanding of mutations role in hematopoietic cells provides an explanation for pathological myeloproliferation, functional involvement of stromal cells in the disease pathogenesis remains poorly understood. The current dogma is that stromal changes are secondary to the cytokine “storm” produced by the hematopoietic clone cells. However, despite therapies targeting the myeloproliferation-sustaining clones, PMF is still regarded as an incurable disease except for patients, who are successful recipients of allogeneic stem cell transplantation. Although the clinical benefits of these inhibitors have been correlated with a marked reduction in serum proinflammatory cytokines produced by the hematopoietic clones, further demonstrating the importance of inflammation in the pathological process, these treatments do not address the role of the altered bone marrow stroma in the pathological process. In this review, we propose hypotheses suggesting that the stroma is inflammatory-imprinted by clonal hematopoietic cells up to a point where it becomes “independent” of hematopoietic cell stimulation, resulting in an inflammatory vicious circle requiring combined stroma targeted therapies. PMID:26640324

  13. Thalidomide-induced hemorrhagic rash in a patient with myelofibrosis and delta-granule storage pool disease.

    PubMed

    Taj, Asma; Abbi, Kamal; Skeel, Roland T

    2015-01-01

    Thalidomide is one of the immunomodulating agents used in current oncology practice. We present a case of hemorrhagic rash induced by thalidomide in a patient with delta granule storage pool disease. The patient was getting thalidomide for underlying myelofibrosis. PMID:24105355

  14. Disease Burden at the Progenitor Level is a feature of Primary Myelofibrosis: A multivariable analysis of 164 JAK2 V617F-positive Myeloproliferative Neoplasm patients

    PubMed Central

    Stein, Brady L.; Williams, Donna M.; Rogers, Ophelia; Isaacs, Mary Ann; Spivak, Jerry L.; Moliterno, Alison R.

    2010-01-01

    Objective Suppression of normal hematopoiesis by the neoplastic clone (clonal dominance) is a feature of the myeloproliferative neoplasms, but the determinants that predict clonal dominance are unknown. The objective of this study was to identify clinical and laboratory variables that associate with the JAK2 V617F CD34+ progenitor allele burden and clonal dominance, which was defined by congruence of the JAK2 V617F CD34+ progenitor and neutrophil allele burdens. Methods A cross-sectional analysis was performed on 164 consecutive JAK2 V617F-positive patients: 30 with essential thrombocytosis (ET), 100 with polycythemia vera (PV), and 34 with myelofibrosis (MF), including 8 post-ETMF and 3 post-PVMF. The JAK2 V617F CD34+ progenitor and neutrophil allele burdens were measured using an allele-specific, quantitative real-time polymerase chain reaction (PCR) assay. Results After adjusting for genotype, sex, age at diagnosis and disease duration, disease type was the strongest predictor of clonal dominance, with the odds ratio being nearly 61.9 times higher for MF patients when compared to ET patients (p<0.001), and 9.7 times higher when compared to PV patients (p=0.002). Additionally, clonal dominance was associated with a clinical phenotype of an increased spleen size (p=0.006), increased white blood cell count (p=0.009), and lower hemoglobin (p <0.001), even after adjusting for disease type and duration. Conclusion These data indicate that loss of wild type clones at the progenitor level is a feature of MF (PMF, post-ETMF, and post-PVMF), presumably due to expansion of the JAK2 V617F clone and that this characteristic is surprisingly independent of JAK2 V617F homozygosity, suggesting that additional genomic lesions may contribute to this unique molecular process that distinguishes MF from ET and PV. PMID:20888389

  15. Interim analysis of safety and efficacy of ruxolitinib in patients with myelofibrosis and low platelet counts

    PubMed Central

    2013-01-01

    Background Ruxolitinib, a Janus kinase 1 and 2 inhibitor, demonstrated improvements in spleen volume, symptoms, and survival over placebo and best available therapy in intermediate-2 or high-risk myelofibrosis patients with baseline platelet counts ≥100 × 109/L in phase III studies. The most common adverse events were dose-dependent anemia and thrombocytopenia, which were anticipated because thrombopoietin and erythropoietin signal through JAK2. These events were manageable, rarely leading to treatment discontinuation. Because approximately one-quarter of MF patients have platelet counts <100 × 109/L consequent to their disease, ruxolitinib was evaluated in this subset of patients using lower initial doses. Interim results of a phase II study of ruxolitinib in myelofibrosis patients with baseline platelet counts of 50-100 × 109/L are reported. Methods Ruxolitinib was initiated at a dose of 5 mg twice daily (BID), and doses could be increased by 5 mg once daily every 4 weeks to 10 mg BID if platelet counts remained adequate. Additional dosage increases required evidence of suboptimal efficacy. Assessments included measurement of spleen volume by MRI, MF symptoms by MF Symptom Assessment Form v2.0 Total Symptom Score [TSS]), Patient Global Impression of Change (PGIC); EORTC QLQ-C30, and safety/tolerability. Results By week 24, 62% of patients achieved stable doses ≥10 mg BID. Median reductions in spleen volume and TSS were 24.2% and 43.8%, respectively. Thrombocytopenia necessitating dose reductions and dose interruptions occurred in 12 and 8 patients, respectively, and occurred mainly in patients with baseline platelet counts ≤75 × 109/L. Seven patients experienced platelet count increases ≥15 × 109/L. Mean hemoglobin levels remained stable over the treatment period. Two patients discontinued for adverse events: 1 for grade 4 retroperitoneal hemorrhage secondary to multiple and suspected pre-existing renal artery aneurysms and 1

  16. Allogeneic stem cell transplant vs.Janus kinase inhibition in the treatment of primary myelofibrosis or myelofibrosis after essential thrombocythemia or polycythemia vera.

    PubMed

    Alchalby, Haefaa; Kröger, Nicolaus

    2014-09-01

    Primary myelofibrosis is one of the Philadelphia chromosome-negative myeloproliferative neoplasms and is the member of that group with the worst survival and the most significant limitations in quality of life. Hepatosplenomegaly due to extramedullary hematopoiesis, constitutional symptoms, and cytopenias are the main manifestations. The natural history is highly variable, and up to 30% of patients can experience acceleration to acute myelogenous leukemia. Conventional therapy is only palliative and not always effective. However, huge advances have been achieved in the past 2 decades toward a better understanding of the pathogenesis of this disease, as well as improved management. Powerful risk stratification systems are now available and can reliably separate the patients into different prognostic categories to aid clinical management. Allogeneic stem cell transplant can offer cure but is still not universally applicable owing to the treatment-related mortality and toxicity. Nevertheless, outcomes of transplant are improving, owing to the introduction of reduced-intensity conditioning regimens and the optimization of remission monitoring techniques and relapse prevention strategies. The discovery of the V617F mutation of JAK2 (Janus kinase 2) and some other molecular aberrations has shed more light on the molecular pathogenesis of the disease and has led to the introduction of novel therapies such as JAK2 inhibitors. In fact, JAK inhibitors have shown promising symptomatic efficacy, and the JAK inhibitor ruxolitinib has also shown a potential survival benefit. Future effort should be made to combine allogeneic stem cell transplant with JAK inhibition. PMID:25486953

  17. Myelofibrosis-When Do We Select Transplantation or Non-transplantation Therapeutic Options?

    PubMed

    Viswabandya, Auro; Devlin, Rebecca; Gupta, Vikas

    2016-02-01

    Janus kinase 1/2 (JAK1/2) inhibitor therapy is effective in alleviating myelofibrosis (MF)-related symptoms. However, at present, the only curative therapy for MF patients is hematopoietic cell transplantation (HCT). The decision of whether to proceed with HCT, which carries significant risks, or continue with JAK inhibitor therapy is a complicated one. Nevertheless, careful assessment of patient, disease, and transplant-related factors can guide this decision on a case-by-case basis. Difficult questions arise in the decision-making process such as age limits, whether lower-risk patients are suitable candidates, and HCT in patients responding well to JAK inhibitor therapy. The optimal timing of transplant is a major dilemma in the management of MF patients who are responding to or are stable on JAK inhibitor therapy. In this paper, we provide our perspective on selection of transplant versus non-transplant therapies in the management of MF. PMID:26659587

  18. Obstructive Uropathy as an Initial Presentation of Primary Myelofibrosis: Case Report and Review of Literature.

    PubMed

    Ganguli, Anirban; Chalokia, Ramandeep Singh; Kaur, Brahm Jyot

    2016-06-01

    Primary myelofibrosis (PMF) is a rare hematological disorder associated with progressive cytopenia and extra-medullary hematopoiesis. Acute kidney injury in this disease has been reported from diverse etiologies such as renal and peri-renal extramedullary hematopoiesis and tumor lysis syndrome. We report a patient who presented with obstructive uropathy from uric acid stones who was incidentally diagnosed with PMF during workup for persistent thrombocytosis and leukocytosis. Marrow histopathology was unique in presenting features of early PMF despite clinical picture mimicking essential thrombocythemia. Despite a common background of hyperuricemia in myeloproliferative neoplasms, AKI resulting from urate nephrolithiasis has seldom been reported in PMF. Published data on this association and clinical management is reviewed briefly. PMID:27408371

  19. Lenalidomide Plus Prednisone Results in Durable Clinical, Histopathologic, and Molecular Responses in Patients With Myelofibrosis

    PubMed Central

    Quintás-Cardama, Alfonso; Kantarjian, Hagop M.; Manshouri, Taghi; Thomas, Deborah; Cortes, Jorge; Ravandi, Farhad; Garcia-Manero, Guillermo; Ferrajoli, Alessandra; Bueso-Ramos, Carlos; Verstovsek, Srdan

    2009-01-01

    Purpose To investigate the safety and efficacy of the combination of lenalidomide and prednisone in patients with myelofibrosis (MF). Patients and Methods Forty patients with MF were treated. Therapy consisted of lenalidomide 10 mg/d (5 mg/d if baseline platelet count < 100 × 109/L) on days 1 through 21 of a 28-day cycle for six cycles, in combination with prednisone 30 mg/d orally during cycle 1, 15 mg/d during cycle 2, and 15 mg/d every other day during cycle 3. Lenalidomide therapy was continued indefinitely in patients exhibiting clinical benefit. Results The median follow-up was 22 months (range, 6 to 27). Responses were recorded in 12 patients (30%) and are ongoing in 10 (25%). The median time to response was 12 weeks (range, 2 to 32). According to the International Working Group for Myelofibrosis Research and Treatment consensus criteria, three patients (7.5%) had partial response and nine patients (22.5%) had clinical improvement durable for a median of 18 months (range, 3.5 to 24+). Overall response rates were 30% for anemia and 42% for splenomegaly. Moreover, 10 of 11 assessable responders who started therapy with reticulin fibrosis grade 4 experienced reductions to at least a score of 2. All eight JAK2V617F–positive responders experienced a reduction of the baseline mutant allele burden, which was greater than 50% in four, including one of whom the mutation became undetectable. Grade 3 to 4 hematologic adverse events included neutropenia (58%), anemia (42%), and thrombocytopenia (13%). Conclusion The combination of lenalidomide and prednisone induces durable clinical, molecular, and pathologic responses in MF. PMID:19720904

  20. Calreticulin mutants in mice induce an MPL-dependent thrombocytosis with frequent progression to myelofibrosis.

    PubMed

    Marty, Caroline; Pecquet, Christian; Nivarthi, Harini; El-Khoury, Mira; Chachoua, Ilyas; Tulliez, Micheline; Villeval, Jean-Luc; Raslova, Hana; Kralovics, Robert; Constantinescu, Stefan N; Plo, Isabelle; Vainchenker, William

    2016-03-10

    Frameshift mutations in the calreticulin (CALR) gene are seen in about 30% of essential thrombocythemia and myelofibrosis patients. To address the contribution of the CALR mutants to the pathogenesis of myeloproliferative neoplasms, we engrafted lethally irradiated recipient mice with bone marrow cells transduced with retroviruses expressing these mutants. In contrast to wild-type CALR, CALRdel52 (type I) and, to a lesser extent, CALRins5 (type II) induced thrombocytosis due to a megakaryocyte (MK) hyperplasia. Disease was transplantable into secondary recipients. After 6 months, CALRdel52-, in contrast to rare CALRins5-, transduced mice developed a myelofibrosis associated with a splenomegaly and a marked osteosclerosis. Monitoring of virus-transduced populations indicated that CALRdel52 leads to expansion at earlier stages of hematopoiesis than CALRins5. However, both mutants still specifically amplified the MK lineage and platelet production. Moreover, a mutant deleted of the entire exon 9 (CALRdelex9) did not induce a disease, suggesting that the oncogenic property of CALR mutants was related to the new C-terminus peptide. To understand how the CALR mutants target the MK lineage, we used a cell-line model and demonstrated that the CALR mutants, but not CALRdelex9, specifically activate the thrombopoietin (TPO) receptor (MPL) to induce constitutive activation of Janus kinase 2 and signal transducer and activator of transcription 5/3/1. We confirmed in c-mpl- and tpo-deficient mice that expression of Mpl, but not of Tpo, was essential for the CALR mutants to induce thrombocytosis in vivo, although Tpo contributes to disease penetrance. Thus, CALR mutants are sufficient to induce thrombocytosis through MPL activation. PMID:26608331

  1. Primary Myelofibrosis

    MedlinePlus

    ... Myeloproliferative Neoplasms Treatment Myelodysplastic/ Myeloproliferative Neoplasms Treatment Chronic Myeloproliferative Neoplasms Treatment (PDQ®)–Patient Version General Information About Chronic ...

  2. Cyclophosphamide and Busulfan Followed by Donor Stem Cell Transplant in Treating Patients With Myelofibrosis, Acute Myeloid Leukemia, or Myelodysplastic Syndrome

    ClinicalTrials.gov

    2014-04-03

    Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Childhood Acute Myeloid Leukemia in Remission; Childhood Myelodysplastic Syndromes; de Novo Myelodysplastic Syndromes; Essential Thrombocythemia; Myelodysplastic Syndrome With Isolated Del(5q); Polycythemia Vera; Previously Treated Myelodysplastic Syndromes; Primary Myelofibrosis; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Secondary Myelofibrosis; Untreated Adult Acute Myeloid Leukemia; Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies

  3. Expanding the SHOC2 Mutation Associated Phenotype of Noonan Syndrome with Loose Anagen Hair: Structural Brain Anomalies and Myelofibrosis

    PubMed Central

    Gripp, Karen W.; Zand, Dina J.; Demmer, Laurie; Anderson, Carol E.; Dobyns, William B.; Zackai, Elaine H.; Denenberg, Elizabeth; Jenny, Kim; Stabley, Deborah L.; Sol-Church, Katia

    2013-01-01

    Noonan syndrome is a heterogenous rasopathy typically presenting with short stature, characteristic facial features, cardiac abnormalities including pulmonic valve stenosis, ASD and hypertrophic cardiomyopathy (HCM), cryptorchidism, ectodermal abnormalities and learning differences. The phenotype is variable, and limited genotype phenotype correlation exists with SOS1 mutations often associated with normal cognition and stature, RAF1 mutations entailing a high HCM risk, and certain PTPN11 mutations predisposing to juvenile myelomonocytic leukemia. The recently identified SHOC2 mutation (p.Ser2Gly) causes Noonan syndrome with loose anagen hair. We report five patients with this mutation. All had skin hyperpigmentation, sparse light colored hair, increased fine wrinkles, ligamentous laxity, developmental delay and 4/4 had a structural cardiac anomaly. Hypotonia and macrocephaly occurred in 4/5 (80%); 3/5 (60%) had polyhydramnios, increased birth weight or required use of a feeding tube. Distinctive brain abnormalities included relative megalencephaly and enlarged subarachnoid spaces suggestive of benign external hydrocephalus, and a relatively small posterior fossa as indicated by a vertical tentorium. The combination of a large brain with a small posterior fossa likely resulted in the high rate of cerebellar tonsillar ectopia (3/4) (75%). Periventricular nodular heterotopia was seen in one patient with a thick and dysplastic corpus callosum. We report on the first hematologic neoplasm, myelofibrosis, in a 2-year-old patient with SHOC2 mutation. Myelofibrosis is exceedingly rare in children and young adults. The absence of a somatic JAK2 mutation, seen in the majority of patients with myelofibrosis, is noteworthy as it suggests that germline or somatic SHOC2 mutations are causally involved in myelofibrosis. PMID:23918763

  4. The impact of ruxolitinib on thrombosis in patients with polycythemia vera and myelofibrosis: a meta-analysis.

    PubMed

    Samuelson, Bethany T; Vesely, Sara K; Chai-Adisaksopha, Chatree; Scott, Bart L; Crowther, Mark; Garcia, David

    2016-09-01

    The Food and Drug Administration approval of ruxolitinib for treatment of myelofibrosis and polycythemia vera has changed the management of patients with myeloproliferative neoplasms. Yet the impact of this therapy on risk of thrombosis, a major cause of morbidity and mortality among these patients, remains unknown. The aim of this study was to evaluate the impact of ruxolitinib on the risk of thrombosis among patients with polycythemia vera or myelofibrosis. Following identification of randomized controlled trials comparing ruxolitinib to standard care or placebo, rates of thrombosis, including venous and arterial thrombosis, were analyzed using fixed effects models. Rates of thrombosis were significantly lower among patients treated with ruxolitinib [risk ratio 0.45, 95% confidence interval (CI) 0.23-0.88]. Subgroup analysis of venous and arterial thrombosis demonstrated similar risk ratios, which did not reach statistical significance (risk ratio 0.46, 95% CI 0.14-1.48 and RR 0.42, 95% CI 0.18-1.01, respectively). In conclusion, our analysis suggests that JAK2 inhibition with ruxolitinib decreases the risk of arterial and/or venous thrombosis in patients with polycythemia vera or myelofibrosis. These findings will require confirmation in a prospective study. PMID:26569516

  5. Primary Myelofibrosis Presenting as Extramedullary Hematopoiesis in a Transplanted Liver Graft: Case Report and Review of the Literature

    PubMed Central

    Mohyuddin, Ghulam Rehman; Yacoub, Abdulraheem

    2016-01-01

    Primary myelofibrosis (PMF) commonly results in extramedullary hematopoiesis (EMH) in the spleen and liver as well as a variety of other organs. We present a first report of a unique presentation of PMF in a liver transplant recipient patient as EMH in the transplanted liver graft. A 76-year-old man with history of cryptogenic cirrhosis received cadaveric liver transplantation in 1996. He maintained a normal graft function and stable hematologic parameters until 2013 when he presented with anemia and progressive fatigue. Extensive work-up did not identify the etiology of the recent decline in his hemoglobin; thus a liver biopsy was done which showed findings of EMH within the sinusoids with increased megakaryocytes, some with atypical morphology. A BM biopsy revealed a hypercellular marrow, moderately increased reticulin fibrosis, and features consistent with primary myelofibrosis. Abdominal imaging showed a normal-size spleen and did not identify any sites of EMH outside of the liver. The diagnosis of myelofibrosis was thus made, and this case demonstrated predominant tropism to a transplanted liver graft with absence of EMH elsewhere. We would thus like to emphasize that findings of EMH in subjects with no preexisting hematologic neoplasm should warrant close follow-up and assessment. PMID:26885416

  6. The Small Molecule Inhibitor G6 Significantly Reduces Bone Marrow Fibrosis and the Mutant Burden in a Mouse Model of Jak2-Mediated Myelofibrosis

    PubMed Central

    Kirabo, Annet; Park, Sung O.; Wamsley, Heather L.; Gali, Meghanath; Baskin, Rebekah; Reinhard, Mary K.; Zhao, Zhizhuang J.; Bisht, Kirpal S.; Keserű, György M.; Cogle, Christopher R.; Sayeski, Peter P.

    2013-01-01

    Philadelphia chromosome–negative myeloproliferative neoplasms, including polycythemia vera, essential thrombocytosis, and myelofibrosis, are disorders characterized by abnormal hematopoiesis. Among these myeloproliferative neoplasms, myelofibrosis has the most unfavorable prognosis. Furthermore, currently available therapies for myelofibrosis have little to no efficacy in the bone marrow and hence, are palliative. We recently developed a Janus kinase 2 (Jak2) small molecule inhibitor called G6 and found that it exhibits marked efficacy in a xenograft model of Jak2-V617F–mediated hyperplasia and a transgenic mouse model of Jak2-V617F–mediated polycythemia vera/essential thrombocytosis. However, its efficacy in Jak2-mediated myelofibrosis has not previously been examined. Here, we hypothesized that G6 would be efficacious in Jak2-V617F–mediated myelofibrosis. To test this, mice expressing the human Jak2-V617F cDNA under the control of the vav promoter were administered G6 or vehicle control solution, and efficacy was determined by measuring parameters within the peripheral blood, liver, spleen, and bone marrow. We found that G6 significantly reduced extramedullary hematopoiesis in the liver and splenomegaly. In the bone marrow, G6 significantly reduced pathogenic Jak/STAT signaling by 53%, megakaryocytic hyperplasia by 70%, and the Jak2 mutant burden by 68%. Furthermore, G6 significantly improved the myeloid to erythroid ratio and significantly reversed the myelofibrosis. Collectively, these results indicate that G6 is efficacious in Jak2-V617F–mediated myelofibrosis, and given its bone marrow efficacy, it may alter the natural history of this disease. PMID:22796437

  7. Up-regulation of MicroRNA 146b is Associated with Myelofibrosis in Myeloproliferative Neoplasms.

    PubMed

    Ha, Jung-Sook; Jung, Hye-Ra

    2015-01-01

    In this study, our goal was to evaluate whether the expressions of microRNA (miR)-150, miR-146b, miR-31 and miR-95 demonstrate primary myelofibrosis (PMF) specificity, associations with fibrosis grade, hematologic phenotypes, or myeloproliferative neoplasm (MPN)-associated mutations. A total of 51 formalin-fixed and paraffin-embedded bone marrow MPN samples, including 15 polycythemia vera (PV), 26 essential thrombocythemia (ET), and 10 PMF, and 24 normal controls were included. The expression of microRNA (miRNA) was detected by quantitative real-time polymerase chain reaction using miRNA specific primers. RNU6-2 was analyzed for all samples as endogenous control for relative quantification. Information for fibrosis, hematologic parameters, Janus kinase 2 (JAK2) V617F, and calreticulin (CALR) mutations was obtained from medical records. Significant increment of miR-146b was detected in PMF compared to normal controls (P=0.008). Moreover, expression of miR-146b tended to increase according to increment of fibrosis grade, and patients with myelofibrosis (MF) grade 3 showed significantly higher expression than patients with MF 0 to 2 (P=0.022, 0.001 and 0.013, respectively) or normal controls (P<0.001). The expression of miR-31 also showed tendency to increase following fibrosis and miR-150 showed up-regulated expression in ET (P=0.015) compared to normal control. There was no relationship between miRNA expression and hematologic indices except miR-95 showed negative correlation with platelet count (P=0.024). There was no significant correlation between miRNA expression and JAK2 V617F or CALR mutation. Up-regulation of miR-146b could be used as a fibrosis-indicating marker and might be helpful in the study of fibrotic mechanism in MPN, as well as other fibrotic diseases. PMID:26116595

  8. JAK2 inhibitors do not affect stem cells present in the spleens of patients with myelofibrosis.

    PubMed

    Wang, Xiaoli; Ye, Fei; Tripodi, Joseph; Hu, Cing Siang; Qiu, Jiajing; Najfeld, Vesna; Novak, Jesse; Li, Yan; Rampal, Raajit; Hoffman, Ronald

    2014-11-01

    Dysregulation of Janus kinase (JAK)-signal transducer and activator of transcription signaling is central to the pathogenesis of myelofibrosis (MF). JAK2 inhibitor therapy in MF patients results in a rapid reduction of the degree of splenomegaly, yet the mechanism underlying this effect remains unknown. The in vitro treatment of splenic and peripheral blood MF CD34(+) cells with the JAK1/2/3 inhibitor, AZD1480, reduced the absolute number of CD34(+), CD34(+)CD90(+), and CD34(+)CXCR4(+) cells as well as assayable hematopoietic progenitor cells (HPCs) irrespective of the JAK2 and calreticulin mutational status. Furthermore, AZD1480 treatment resulted in only a modest reduction in the proportion of HPCs that were JAK2V617F(+) or had a chromosomal abnormality. To study the effect of the drug on MF stem cells (MF-SCs), splenic CD34(+) cells were treated with AZD1480 and transplanted into immunodeficient mice. JAK2 inhibitor therapy did not affect the degree of human cell chimerism or the proportion of malignant donor cells. These data indicate that JAK2 inhibitor treatment affects a subpopulation of MF-HPCs, while sparing another HPC subpopulation as well as MF-SCs. This pattern of activity might account for the reduction in spleen size observed with JAK2 inhibitor therapy as well as the rapid increase in spleen size observed frequently with its discontinuation. PMID:25193869

  9. JAK2 inhibitors do not affect stem cells present in the spleens of patients with myelofibrosis

    PubMed Central

    Wang, Xiaoli; Ye, Fei; Tripodi, Joseph; Hu, Cing Siang; Qiu, Jiajing; Najfeld, Vesna; Novak, Jesse; Li, Yan; Rampal, Raajit

    2014-01-01

    Dysregulation of Janus kinase (JAK)–signal transducer and activator of transcription signaling is central to the pathogenesis of myelofibrosis (MF). JAK2 inhibitor therapy in MF patients results in a rapid reduction of the degree of splenomegaly, yet the mechanism underlying this effect remains unknown. The in vitro treatment of splenic and peripheral blood MF CD34+ cells with the JAK1/2/3 inhibitor, AZD1480, reduced the absolute number of CD34+, CD34+CD90+, and CD34+CXCR4+ cells as well as assayable hematopoietic progenitor cells (HPCs) irrespective of the JAK2 and calreticulin mutational status. Furthermore, AZD1480 treatment resulted in only a modest reduction in the proportion of HPCs that were JAK2V617F+ or had a chromosomal abnormality. To study the effect of the drug on MF stem cells (MF-SCs), splenic CD34+ cells were treated with AZD1480 and transplanted into immunodeficient mice. JAK2 inhibitor therapy did not affect the degree of human cell chimerism or the proportion of malignant donor cells. These data indicate that JAK2 inhibitor treatment affects a subpopulation of MF-HPCs, while sparing another HPC subpopulation as well as MF-SCs. This pattern of activity might account for the reduction in spleen size observed with JAK2 inhibitor therapy as well as the rapid increase in spleen size observed frequently with its discontinuation. PMID:25193869

  10. The role of zinc protoporphyrin measurement in the differentiation between primary myelofibrosis and essential thrombocythaemia.

    PubMed

    Metzgeroth, Georgia; Kanders, Eva-Maria; Erben, Philipp; Hofmann, Wolf-Karsten; Hastka, Jan

    2011-04-01

    The differentiation between primary myelofibrosis (PMF) and essential thrombocythaemia (ET) may be difficult especially in early-stage disease. In PMF, increased levels of inflammatory cytokines induce impaired iron utilisation and disturbed erythropoiesis. In conditions with impaired iron support to erythropoiesis, zinc protoporphyrin (ZPP) is produced instead of heme. Here, we investigate whether ZPP concentration can be useful in the differentiation between PMF and ET. Seventy newly diagnosed patients (PMF, n=24; ET, n=46) were analysed. Intraerythrocytic ZPP concentration (normal≤40 μmol/mol heme) was measured by an Aviv front-face haematofluorometer. In PMF, ZPP concentrations were significantly increased when compared to ET (99±37 μmol/mol heme vs. 36±13 μmol/mol heme, p<0.0001). There was also a significant difference between early-stage PMF and advanced disease (77±30 μmol/mol heme vs. 122±31 μmol/mol heme, p=0.003). ZPP>76 μmol/mol heme as observed in 71% of PMF patients were not seen in ET. In PMF patients responding to immunosuppressive treatment (n=4), the increase in haemoglobin was accompanied by declining ZPP. In summary, by detecting the disturbed iron metabolism common in PMF, ZPP may assist in the differentiation between PMF and ET. Concentrations>60 μmol/mol heme are unlikely in ET if iron deficiency is excluded. ZPP determination is also useful for monitoring the effect of therapy in PMF. PMID:20922526

  11. Transcriptome analysis of bone marrow mesenchymal stromal cells from patients with primary myelofibrosis

    PubMed Central

    Martinaud, Christophe; Desterke, Christophe; Konopacki, Johanna; Vannucchi, Alessandro M.; Pieri, Lisa; Guglielmelli, Paola; Dupriez, Brigitte; Ianotto, Jean-Christophe; Boutin, Laetitia; Lataillade, Jean-Jacques; Le Bousse-Kerdilès, Marie-Caroline

    2015-01-01

    Primary myelofibrosis (PMF) is a clonal myeloproliferative neoplasm whose severity and treatment complexity are attributed to the presence of bone marrow (BM) fibrosis and alterations of stroma impairing the production of normal blood cells. Despite the recently discovered mutations including the JAK2V617F mutation in about half of patients, the primitive event responsible for the clonal proliferation is still unknown. In the highly inflammatory context of PMF, the presence of fibrosis associated with a neoangiogenesis and an osteosclerosis concomitant to the myeloproliferation and to the increase number of circulating hematopoietic progenitors suggests that the crosstalk between hematopoietic and stromal cells is deregulated in the PMF BM microenvironmental niches. Within these niches, mesenchymal stromal cells (BM-MSC) play a hematopoietic supportive role in the production of growth factors and extracellular matrix which regulate the proliferation, differentiation, adhesion and migration of hematopoietic stem/progenitor cells. A transcriptome analysis of BM-MSC in PMF patients will help to characterize their molecular alterations and to understand their involvement in the hematopoietic stem/progenitor cell deregulation that features PMF. PMID:26484208

  12. Ruxolitinib is effective in patients with intermediate-1 risk myelofibrosis: a summary of recent evidence

    PubMed Central

    Harrison, Claire N.; Talpaz, Moshe; Mead, Adam J.

    2016-01-01

    Abstract Ruxolitinib is the only therapy with an approved indication for myelofibrosis (MF), a myeloproliferative neoplasm associated with progressive bone marrow fibrosis and extramedullary hematopoiesis. Although the pivotal phase 3 COMFORT studies included only patients with intermediate-2 or high-risk MF, the US indication includes all patients with intermediate- or high-risk disease. Data from recent nonrandomized studies confirm that the benefits of ruxolitinib established in the COMFORT studies in terms of spleen size reduction and symptom improvement also extend to patients with intermediate-1 risk MF, who tend to have less advanced disease than patients with higher-risk MF. Given the disease-modifying potential of ruxolitinib therapy, timely initiation of ruxolitinib therapy may not only improve patients’ current clinical status but also lead to better long-term outcomes. The decision of whether or when to initiate ruxolitinib treatment should be based on the expected benefit–risk ratio for each patient, specifically considering potential adverse effects. PMID:27463690

  13. Ruxolitinib is effective in patients with intermediate-1 risk myelofibrosis: a summary of recent evidence.

    PubMed

    Harrison, Claire N; Talpaz, Moshe; Mead, Adam J

    2016-10-01

    Ruxolitinib is the only therapy with an approved indication for myelofibrosis (MF), a myeloproliferative neoplasm associated with progressive bone marrow fibrosis and extramedullary hematopoiesis. Although the pivotal phase 3 COMFORT studies included only patients with intermediate-2 or high-risk MF, the US indication includes all patients with intermediate- or high-risk disease. Data from recent nonrandomized studies confirm that the benefits of ruxolitinib established in the COMFORT studies in terms of spleen size reduction and symptom improvement also extend to patients with intermediate-1 risk MF, who tend to have less advanced disease than patients with higher-risk MF. Given the disease-modifying potential of ruxolitinib therapy, timely initiation of ruxolitinib therapy may not only improve patients' current clinical status but also lead to better long-term outcomes. The decision of whether or when to initiate ruxolitinib treatment should be based on the expected benefit-risk ratio for each patient, specifically considering potential adverse effects. PMID:27463690

  14. Unrelated cord blood transplantation for patients with primary or secondary myelofibrosis.

    PubMed

    Robin, Marie; Giannotti, Federica; Deconinck, Eric; Mohty, Mohamad; Michallet, Mauricette; Sanz, Guillermo; Chevallier, Patrice; Cahn, Jean-Yves; Legrand, Faezeh; Rovira, Montserrat; Passweg, Jakob; Sierra, Jorge; Nguyen, Stephanie; Maillard, Natacha; Yakoub-Agha, Ibrahim; Linkesch, Werner; Cannell, Paul; Marcatti, Magda; Bay, Jacques-Olivier; Chalandon, Yves; Kröger, Nicolaus; Gluckman, Eliane; Rocha, Vanderson; Olavarria, Eduardo; Ruggeri, Annalisa

    2014-11-01

    To determine whether umbilical cord blood transplantation (UCBT) is an alternative cure for myelofibrosis (MF), we evaluated 35 UCBTs reported to Eurocord. Seven patients had secondary acute myeloid leukemia (AML) at UCBT, and median age at UCBT was 54 years. Twenty-four patients received a reduced-intensity conditioning (RIC) regimen, and 17 of 35 patients received total body irradiation (2 to 12 Gy)-fludarabine-cyclophosphamide (TCF) conditioning. The median follow-up was 24 months. The cumulative incidence of neutrophil recovery at 60 days was 80%. Fifteen patients relapsed after UCBT. The 2-year overall survival and event-free-survival (EFS) rates were 44% and 30%, respectively. All patients given TCF achieved neutrophil and platelet recovery, and the use of TCF was associated with superior EFS in the RIC population (44% versus 0%, P = .001). Patients with transformation to AML had similar outcomes to patients with less advanced stages. In conclusion, despite graft failure remaining a major concern, the role of UCBT in the management of MF, especially using RIC TCF-based regimens, deserves further investigation to improve results. PMID:24946719

  15. Autoimmune Myelofibrosis in Systemic Lupus Erythematosus Report of Two Cases and Review of the Literature.

    PubMed

    Koduri, Prasad R; Parvez, Mohammad; Kaza, Sashidhar; Vanajakshi, S

    2016-09-01

    Autoimmune myelofibrosis (AIMF) is a rare entity of steroid-responsive bone marrow fibrosis that accompanies a variety of autoimmune diseases, particularly systemic lupus erythematosus (SLE). Rarely it may occur in patients with autoimmune markers but no definable autoimmune disease (Primary-AIMF). We report the cases of two young women with SLE-associated AIMF (SLE-AIMF). The first patient was a young woman who had pancytopenia, massive splenomegaly and reticulin fibrosis in the marrow biopsy. The pancytopenia and splenomegaly resolved completely within weeks of treatment with corticosteroids. Repeat marrow biopsy showed marked regression of marrow fibrosis. The second patient was a young woman with fever, anasarca, bicytopenia and reticulin fibrosis in the marrow biopsy. Steroid therapy resulted in rapid clinical improvement and resolution of pancytopenia. A review of the literature revealed a total of 30 patients with SLE-AIMF reported to-date. Patients with SLE-AIMF are young women with SLE and blood cytopenia who are found to have increased bone marrow reticulin on marrow biopsy. Steroid therapy results in rapid hematological recovery and regression of marrow fibrosis. Whether AIMF is one of several hematological complications of SLE, or represents a unique and distinct subset of patients with SLE in not clear. Prospective studies with longer follow-up are needed to better define the prevalence and clinical spectrum of SLE-AIMF. PMID:27429532

  16. Allo-SCT for myelofibrosis: reversing the chronic phase in the JAK inhibitor era?

    PubMed

    Tamari, R; Mughal, T I; Rondelli, D; Hasserjian, R; Gupta, V; Odenike, O; Fauble, V; Finazzi, G; Pane, F; Mascarenhas, J; Prchal, J; Giralt, S; Hoffman, R

    2015-05-01

    At present, allo-SCT is the only curative treatment for patients with myelofibrosis (MF). Unfortunately, a significant proportion of candidate patients are considered transplant ineligible due to their poor general condition and advanced age at the time of diagnosis. The approval of the first JAK inhibitor, ruxolitinib, for patients with advanced MF in 2011 has had a qualified impact on the treatment algorithm. The drug affords substantial improvement in MF-associated symptoms and splenomegaly but no major effect on the natural history. There has, therefore, been considerable support for assessing the drug's candidacy in the peritransplant period. The drug's precise impact on clinical outcome following allo-SCT is currently not known; nor are the drug's long-term efficacy and safety known. Considering the rarity of MF and the small proportion of patients who undergo allo-SCT, well designed collaborative efforts are required. In order to address some of the principal challenges, an expert panel of laboratory and clinical experts in this field was established, and an independent workshop held during the 54th American Society of Hematology Annual Meeting in New Orleans, USA on 6 December 2013, and the European Hematology Association's Annual Meeting in Milan, Italy on 13 June 2014. This document summarizes the results of these efforts. PMID:25665047

  17. Pros and cons of splenectomy in patients with myelofibrosis undergoing stem cell transplantation.

    PubMed

    Li, Z; Deeg, H J

    2001-03-01

    During fetal development, the spleen is a major hemopoietic organ. In the adult human, this task is relinquished to the bone marrow. However, under the stress of certain pathologic conditions, extramedullary hemopoiesis may again occur in the spleen. This is especially true for diseases of the marrow, in particular, myeloproliferative disorders such as agnogenic myeloid metaplasia, which is associated with severe fibrosis of the marrow space. At the same time, the spleen sequesters blood cells and contributes to peripheral blood cytopenias, which may improve following splenectomy. However, success is unpredictable, and the operative mortality of splenectomy is on the order of 10%. As a growing number of patients undergo hemopoietic stem cell transplantation as definitive therapy for myelofibrosis, the decision on splenectomy has additional ramifications since the spleen plays an important role in the kinetics of engraftment of donor cells and in immune reconstitution. We conclude from our analysis of available information that the benefit of splenectomy is difficult to predict, although after transplantation splenectomized patients have faster hemopoietic recovery. It appears that the most important indication for splenectomy in these patients is the relief of symptoms from massive spleen enlargement. PMID:11237072

  18. Optimizing management of ruxolitinib in patients with myelofibrosis: the need for individualized dosing

    PubMed Central

    2013-01-01

    Ruxolitinib, an oral JAK1 and JAK2 inhibitor, is approved in the US for patients with intermediate or high-risk myelofibrosis (MF), a chronic neoplasm associated with aberrant myeloproliferation, progressive bone marrow fibrosis, splenomegaly, and burdensome symptoms. Phase III clinical studies have shown that ruxolitinib reduces splenomegaly and alleviates MF-related symptoms, with concomitant improvements in quality of life measures, for the overwhelming majority of treated patients. In addition, ruxolitinib provided an overall survival advantage as compared with either placebo or what was previously considered best available therapy in the two phase III studies. The most common adverse events with ruxolitinib treatment include dose-dependent anemia and thrombocytopenia, which are expected based on its mechanism of action. Experience from the phase III studies shows that these hematologic events can be managed effectively with dose modifications, temporary treatment interruptions, as well as red blood cell transfusions in the case of anemia and, importantly, are rarely cause for permanent treatment discontinuation. This review summarizes data supporting appropriate individualized patient management through careful monitoring of blood counts and dose titration as needed in order to maximize treatment benefit. PMID:24283870

  19. Lipocalin produced by myelofibrosis cells affects the fate of both hematopoietic and marrow microenvironmental cells.

    PubMed

    Lu, Min; Xia, Lijuan; Liu, Yen-Chun; Hochman, Tsivia; Bizzari, Laetizia; Aruch, Daniel; Lew, Jane; Weinberg, Rona; Goldberg, Judith D; Hoffman, Ronald

    2015-08-20

    Myelofibrosis (MF) is characterized by cytopenias, constitutional symptoms, splenomegaly, and marrow histopathological abnormalities (fibrosis, increased microvessel density, and osteosclerosis). The microenvironmental abnormalities are likely a consequence of the elaboration of a variety of inflammatory cytokines generated by malignant megakaryocytes and monocytes. We observed that levels of a specific inflammatory cytokine, lipocalin-2 (LCN2), were elevated in the plasmas of patients with myeloproliferative neoplasms (MF > polycythemia vera or essential thrombocythemia) and that LCN2 was elaborated by MF myeloid cells. LCN2 generates increased reactive oxygen species, leading to increased DNA strand breaks and apoptosis of normal, but not MF, CD34(+) cells. Furthermore, incubation of marrow adherent cells or mesenchymal stem cells with LCN2 increased the generation of osteoblasts and fibroblasts, but not adipocytes. LCN2 priming of mesenchymal stem cells resulted in the upregulation of RUNX2 gene as well as other genes that are capable of further affecting osteoblastogenesis, angiogenesis, and the deposition of matrix proteins. These data indicate that LCN2 is an additional MF inflammatory cytokine that likely contributes to the creation of a cascade of events that results in not only a predominance of the MF clone but also a dysfunctional microenvironment. PMID:26022238

  20. Pruritus in primary myelofibrosis: management options in the era of JAK inhibitors.

    PubMed

    Vaa, Brianna E; Tefferi, Ayalew; Gangat, Naseema; Pardanani, Animesh; Lasho, Terra L; Finke, Christy M; Wolanskyj, Alexandra P

    2016-06-01

    Primary myelofibrosis (PMF)-associated pruritus is often severe and requires treatment. Fifty-one patients with bone marrow-proven PMF with associated pruritus were identified from a primary cohort of patients with PMF (n = 566) seen at our institution. We conducted a retrospective review of the clinical characteristics, severity of pruritus, type of treatment, and response of these patients. Thirty-two out of 51 patients (63 %) reported severe PMF-associated pruritus and required a total of 108 treatment episodes, with complete response (CR), partial response (PR) and no response (NR) observed in 22, 23, and 55 % of episodes, respectively. The most common treatment categories included JAK inhibitors (n = 19), anti-depressants (n = 18), and antihistamines (n = 17). Highest CR rates were observed in patients treated with a JAK inhibitor (53 %) and immunomodulatory drugs (IMiDS (50 %)). Emerging targeted therapies may result in better symptom control and higher response rates in patients suffering from severe PMF-associated pruritus. PMID:27106700

  1. Outcomes of Allogeneic Hematopoietic Cell Transplantation in Patients with Myelofibrosis with Prior Exposure to Janus Kinase 1/2 Inhibitors.

    PubMed

    Shanavas, Mohamed; Popat, Uday; Michaelis, Laura C; Fauble, Veena; McLornan, Donal; Klisovic, Rebecca; Mascarenhas, John; Tamari, Roni; Arcasoy, Murat O; Davies, James; Gergis, Usama; Ukaegbu, Oluchi C; Kamble, Rammurti T; Storring, John M; Majhail, Navneet S; Romee, Rizwan; Verstovsek, Srdan; Pagliuca, Antonio; Vasu, Sumithira; Ernst, Brenda; Atenafu, Eshetu G; Hanif, Ahmad; Champlin, Richard; Hari, Paremeswaran; Gupta, Vikas

    2016-03-01

    The impact of Janus kinase (JAK) 1/2 inhibitor therapy before allogeneic hematopoietic cell transplantation (HCT) has not been studied in a large cohort in myelofibrosis (MF). In this retrospective multicenter study, we analyzed outcomes of patients who underwent HCT for MF with prior exposure to JAK1/2 inhibitors. One hundred consecutive patients from participating centers were analyzed, and based on clinical status and response to JAK1/2 inhibitors at the time of HCT, patients were stratified into 5 groups: (1) clinical improvement (n = 23), (2) stable disease (n = 31), (3) new cytopenia/increasing blasts/intolerance (n = 15), (4) progressive disease: splenomegaly (n = 18), and (5) progressive disease: leukemic transformation (LT) (n = 13). Overall survival (OS) at 2 years was 61% (95% confidence interval [CI], 49% to 71%). OS was 91% (95% CI, 69% to 98%) for those who experienced clinical improvement and 32% (95% CI, 8% to 59%) for those who developed LT on JAK1/2 inhibitors. In multivariable analysis, response to JAK1/2 inhibitors (P = .03), dynamic international prognostic scoring system score (P = .003), and donor type (P = .006) were independent predictors of survival. Among the 66 patients who remained on JAK1/2 inhibitors until stopped for HCT, 2 patients developed serious adverse events necessitating delay of HCT and another 8 patients had symptoms with lesser severity. Adverse events were more common in patients who started tapering or abruptly stopped their regular dose ≥6 days before conditioning therapy. We conclude that prior exposure to JAK1/2 inhibitors did not adversely affect post-transplantation outcomes. Our data suggest that JAK1/2 inhibitors should be continued near to the start of conditioning therapy. The favorable outcomes of patients who experienced clinical improvement with JAK1/2 inhibitor therapy before HCT were particularly encouraging, and need further prospective validation. PMID:26493563

  2. Tie2 Expressing Monocytes in the Spleen of Patients with Primary Myelofibrosis

    PubMed Central

    Campanelli, Rita; Fois, Gabriela; Catarsi, Paolo; Poletto, Valentina; Villani, Laura; Erba, Benedetta Gaia; Maddaluno, Luigi; Jemos, Basilio; Salmoiraghi, Silvia; Guglielmelli, Paola; Abbonante, Vittorio; Di Buduo, Christian Andrea; Balduini, Alessandra; Iurlo, Alessandra; Barosi, Giovanni; Rosti, Vittorio; Massa, Margherita

    2016-01-01

    Primary myelofibrosis (PMF) is a Philadelphia-negative (Ph−) myeloproliferative disorder, showing abnormal CD34+ progenitor cell trafficking, splenomegaly, marrow fibrosis leading to extensive extramedullary haematopoiesis, and abnormal neoangiogenesis in either the bone marrow or the spleen. Monocytes expressing the angiopoietin-2 receptor (Tie2) have been shown to support abnormal angiogenic processes in solid tumors through a paracrine action that takes place in proximity to the vessels. In this study we investigated the frequency of Tie2 expressing monocytes in the spleen tissue samples of patients with PMF, and healthy subjects (CTRLs), and evaluated their possible role in favouring spleen angiogenesis. We show by confocal microscopy that in the spleen tissue of patients with PMF, but not of CTRLs, the most of the CD14+ cells are Tie2+ and are close to vessels; by flow cytometry, we found that Tie2 expressing monocytes were Tie2+CD14lowCD16brightCDL62−CCR2− (TEMs) and their frequency was higher (p = 0.008) in spleen tissue-derived mononuclear cells (MNCs) of patients with PMF than in spleen tissue-derived MNCs from CTRLs undergoing splenectomy for abdominal trauma. By in vitro angiogenesis assay we evidenced that conditioned medium of immunomagnetically selected spleen tissue derived CD14+ cells of patients with PMF induced a denser tube like net than that of CTRLs; in addition, CD14+Tie2+ cells sorted from spleen tissue derived single cell suspension of patients with PMF show a higher expression of genes involved in angiogenesis than that found in CTRLs. Our results document the enrichment of Tie2+ monocytes expressing angiogenic genes in the spleen of patients with PMF, suggesting a role for these cells in starting/maintaining the pathological angiogenesis in this organ. PMID:27281335

  3. A 7-Gene Signature Depicts the Biochemical Profile of Early Prefibrotic Myelofibrosis.

    PubMed

    Skov, Vibe; Burton, Mark; Thomassen, Mads; Stauffer Larsen, Thomas; Riley, Caroline H; Brinch Madelung, Ann; Kjær, Lasse; Bondo, Henrik; Stamp, Inger; Ehinger, Mats; Dahl-Sørensen, Rasmus; Brochmann, Nana; Nielsen, Karsten; Thiele, Jürgen; Jensen, Morten K; Weis Bjerrum, Ole; Kruse, Torben A; Hasselbalch, Hans Carl

    2016-01-01

    Recent studies have shown that a large proportion of patients classified as essential thrombocythemia (ET) actually have early primary prefibrotic myelofibrosis (prePMF), which implies an inferior prognosis as compared to patients being diagnosed with so-called genuine or true ET. According to the World Health Organization (WHO) 2008 classification, bone marrow histology is a major component in the distinction between these disease entities. However, the differential diagnosis between them may be challenging and several studies have not been able to distinguish between them. Most lately, it has been argued that simple blood tests, including the leukocyte count and plasma lactate dehydrogenase (LDH) may be useful tools to separate genuine ET from prePMF, the latter disease entity more often being featured by anemia, leukocytosis and elevated LDH. Whole blood gene expression profiling was performed in 17 and 9 patients diagnosed with ET and PMF, respectively. Using elevated LDH obtained at the time of diagnosis as a marker of prePMF, a 7-gene signature was identified which correctly predicted the prePMF group with a sensitivity of 100% and a specificity of 89%. The 7 genes included MPO, CEACAM8, CRISP3, MS4A3, CEACAM6, HEMGN, and MMP8, which are genes known to be involved in inflammation, cell adhesion, differentiation and proliferation. Evaluation of bone marrow biopsies and the 7-gene signature showed a concordance rate of 71%, 79%, 62%, and 38%. Our 7-gene signature may be a useful tool to differentiate between genuine ET and prePMF but needs to be validated in a larger cohort of "ET" patients. PMID:27579896

  4. Anti-thymocyte globulin-induced hyperbilirubinemia in patients with myelofibrosis undergoing allogeneic hematopoietic cell transplantation.

    PubMed

    Ecsedi, Matyas; Schmohl, Jörg; Zeiser, Robert; Drexler, Beatrice; Halter, Jörg; Medinger, Michael; Duyster, Justus; Kanz, Lothar; Passweg, Jakob; Finke, Jürgen; Bethge, Wolfgang; Lengerke, Claudia

    2016-10-01

    Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only curative treatment option for myelofibrosis (MF) despite the emergence of novel targeted therapies. To reduce graft rejection and graft-versus-host disease (GvHD), current allo-HCT protocols often include in vivo T lymphocyte depletion using polyclonal anti-thymocyte globulin (ATG). Shortly after ATG administration, an immediate inflammatory response with fever, chills, and laboratory alterations such as cytopenias, elevation of serum C-reactive protein, bilirubin, and transaminases can develop. Here, we explore whether MF patients, who commonly exhibit extramedullary hematopoiesis in the liver, might be particularly susceptible to ATG-induced liver toxicity. To test this hypothesis, we analyzed 130 control and 94 MF patients from three transplant centers treated with or without ATG during the allo-HCT conditioning regimen. Indeed, hyperbilirubinemia was found in nearly every MF patient treated with ATG (MF-ATG 54/60 = 90 %) as compared to non-ATG treated MF (MF-noATG 15/34 = 44.1 %, p < 0.001) and respectively ATG-treated non-MF patients of the control group (control-ATG, 43/77 = 56 %, p < 0.001). In contrast, transaminases were only inconsistently elevated. Hyperbilirubinemia was in most cases self-limiting and not predictive of increased incidence of non-relapse mortality, hepatic sinusoidal obstruction syndrome (SOS) or liver GvHD. In sum, awareness of this stereotypic bilirubin elevation in MF patients treated with ATG provides a relatively benign explanation for hyperbilirubinemia occurring in these patients during the early transplant. However, attention to drug levels of biliary excreted drugs is warranted, since altered bile flow may influence their clearance and enhance toxicity (e.g., busulfan, antifungal agents). PMID:27480090

  5. Overcoming treatment challenges in myelofibrosis and polycythemia vera: the role of ruxolitinib.

    PubMed

    Bryan, Jeffrey C; Verstovsek, Srdan

    2016-06-01

    Myelofibrosis (MF) and polycythemia vera (PV) are BCR-ABL1-negative myeloproliferative neoplasms associated with somatic hematopoietic stem cell mutations leading to over activation of JAK-STAT signaling. MF and PV are pathogenically related and share specific clinical features such as splenomegaly and constitutional symptoms. The MF phenotype is dominated by the effects of progressive bone marrow fibrosis resulting in shortened survival. In contrast, elevated thrombosis risk due to erythrocytosis is the primary clinical concern in PV. Ruxolitinib, an oral JAK1/JAK2 inhibitor, is approved in the USA for the treatment of patients with intermediate- or high-risk MF and patients with PV who have had an inadequate response to or are intolerant of hydroxyurea. For MF, results of two phase III studies demonstrated that ruxolitinib therapy reduced spleen volume and MF-related symptom burden, improved quality-of-life measures, and was associated with prolonged overall survival. Treatment benefits were generally sustained with continued therapy. Dose-dependent cytopenias were common but generally manageable with transfusions (for anemia), dose reduction, or treatment interruption. Optimal dosing management is critical to maintain long-term treatment benefit, because cessation of therapy resulted in rapid return of symptoms to baseline levels. Results of the phase III PV trial showed that ruxolitinib was significantly more effective than standard therapy in controlling hematocrit levels and improving splenomegaly and PV-related symptoms. Only 1 of 110 patients in the ruxolitinib arm compared with 6 of 112 patients in the control arm experienced a thromboembolic event through week 32. Grade ≥3 cytopenias were uncommon. PMID:27017614

  6. Homozygous calreticulin mutations in patients with myelofibrosis lead to acquired myeloperoxidase deficiency.

    PubMed

    Theocharides, Alexandre P A; Lundberg, Pontus; Lakkaraju, Asvin K K; Lysenko, Veronika; Myburgh, Renier; Aguzzi, Adriano; Skoda, Radek C; Manz, Markus G

    2016-06-23

    The pathogenesis of acquired myeloperoxidase (MPO) deficiency, a rare phenomenon observed in patients with Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), is unknown. MPO is a glycoprotein (GP) chaperoned by calreticulin (CALR) in the endoplasmic reticulum. Mutations in CALR are frequently found in patients with myelofibrosis (MF) and essential thrombocythemia (ET) with nonmutated Janus kinase 2 (JAK2). We hypothesized that acquired MPO deficiency in MPN could be associated with the presence of CALR mutations. A cohort of 317 patients with MPN (142 polycythemia vera [PV], 94 ET, and 81 MF) was screened for MPO deficiency. MPO deficiency was observed in 6/81 MF patients (7.4%), but not in PV or ET patients. Susceptibility to infections had been documented in 2/6 (33%) MPO-deficient patients. Five out of 6 patients with MPO deficiency carried a homozygous CALR mutation and were also deficient in eosinophilic peroxidase (EPX). In contrast, 1 patient with MF, a JAK2-V617F mutation, and MPO deficiency, carried 2 previously reported MPO mutations and showed normal EPX activity. Patients with homozygous CALR mutations had reduced MPO protein, but normal MPO messenger RNA (mRNA) levels supporting a posttranscriptional defect in MPO production. Finally, we demonstrate in vitro that in the absence of CALR, immature MPO protein precursors are degraded in the proteasome. Therefore, 4 decades after the first description of acquired MPO deficiency in MPN, we provide the molecular correlate associated with this phenomenon and evidence that CALR mutations can affect the biosynthesis of GPs. PMID:27013444

  7. The Clinical Significance of IDH Mutations in Essential Thrombocythemia and Primary Myelofibrosis

    PubMed Central

    Yonal-Hindilerden, Ipek; Daglar-Aday, Aynur; Hindilerden, Fehmi; Akadam-Teker, Basak; Yilmaz, Ceylan; Nalcaci, Meliha; Yavuz, Akif Selim; Sargin, Deniz

    2016-01-01

    Background Limited data exist regarding impact of IDH mutations in Philadelphia-negative myeloproliferative neoplasms (Ph-negative MPNs). Prognostic significance of IDH mutations was asessed in 184 Ph-negative MPN patients - 107 essential thrombocythemia (ET) and 77 primary myelofibrosis (PMF). Methods High-resolution melting (HRM) analysis was used to detect IDH1 and IDH2 mutations. Results PMF and ET patients showed no significant difference for prevalence of IDH mutations. Mutant IDH (IDH1 or IDH2) was documented in five of PMF (6.5%) and two of ET patients (1.9%). IDH mutations in ET patients included one IDH1 R132C and one IDH2 R140Q. Of the five IDH-mutated PMF patients, four (80%) displayed IDH1 (three IDH1 R132C and one IDH1 R132S) and one (20%) carried IDH2 (IDH2 R140Q) mutation. Sixty percent (three in five) of IDH-mutated PMF patients carried JAK2V617F with following allele burdens: 31-50%, 5-12.5% and 31-50%, respectively. Three of 77 PMF patients (3.9%) simultaneously harbored IDH and JAK2V617F mutations. IDH mutations in PMF showed a trend towards higher rate in females (100% and 52.8%, respectively). Bleeding complications were significantly higher in IDH-mutated PMF patients compared to IDH wild-type counterparts. Trend towards a lower prevalance of acetylsalicylic acid (ASA) use was present in IDH mutant PMF patients compared to wild-type counterparts (20% and 63.9%, respectively). Death rate was higher in IDH-mutated PMF patients compared to IDH wild-type PMF patients (60% and 15.3%). In univariate analysis, a significantly shorter leukemia-free survival (LFS) was observed in IDH-mutated PMF patients. Conclusions We conclude that IDH mutations indicate a risk for leukemic transformation in PMF. PMID:26668680

  8. Critical appraisal of the role of ruxolitinib in myeloproliferative neoplasm-associated myelofibrosis

    PubMed Central

    Barosi, Giovanni; Rosti, Vittorio; Gale, Robert Peter

    2015-01-01

    The recent approval of molecular-targeted therapies for myeloproliferative neoplasm-associated myelofibrosis (MPN-MF) has dramatically changed its therapeutic landscape. Ruxolitinib, a JAK1/JAK2 tyrosine kinase inhibitor, is now widely used for first- and second-line therapy in persons with MPN-MF, especially those with disease-related splenomegaly, intermediate- or high-risk disease, and constitutional symptoms. The goal of this work is to critically analyze data supporting use of ruxolitinib in the clinical settings approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA). We systematically reviewed the literature and analyzed the risk of biases in the two randomized studies (COMFORT I and COMFORT II) on which FDA and EMA approval was based. Our strategy was to apply the Grading of Recommendation, Assessment, Development and Evaluation (GRADE) approach by evaluating five dimensions of evidence: (1) overall risk of bias, (2) imprecision, (3) inconsistency, (4) indirectness, and (5) publication bias. Based on these criteria, we downgraded the evidence from the COMFORT I and COMFORT II trials for performance, attrition, and publication bias. In the disease-associated splenomegaly sphere, we upgraded the quality of evidence because of large effect size but downgraded it because of comparator choice and outcome indirectness (quality of evidence, low). In the sphere of treating persons with intermediate- or high-risk disease, we downgraded the evidence because of imprecision in effect size measurement and population indirectness. In the sphere of disease-associated symptoms, we upgraded the evidence because of the large effect size, but downgraded it because of comparator indirectness (quality of evidence, moderate). In conclusion, using the GRADE technique, we identified factors affecting the quality of evidence that were otherwise unstated. Identifying and evaluating these factors should influence the confidence with which physicians

  9. CXCL12 Influences the Development of Extramedullary Hematopoiesis in the Spleens of Myelofibrosis Patients

    PubMed Central

    Wang, Xiaoli; Cho, Sool Yeon; Hu, Cing Siang; Chen, Daniel; Roboz, John; Hoffman, Ronald

    2014-01-01

    Myelofibrosis (MF) is characterized by the constitutive mobilization of hematopoietic stem cells (HSC) and progenitor cells (HPC) and the establishment of extramedullary hematopoiesis (EMH). The mechanisms underlying this abnormal HSC/HPC trafficking pattern remain poorly understood. We demonstrated that both splenic and peripheral blood (PB) MF CD34+ cells equally share a defective ability to home to the marrow but not the spleens of NOD/SCID mice. This trafficking pattern could not be attributed to discordant expression of integrins or chemokine receptors other than the down-regulation of CXCR4 by both PB and splenic MF CD34+ cells. The number of both splenic MF CD34+ cells and HPCs that migrated towards splenic MF plasma was, however, significantly greater than the number that migrated towards PB MF plasma. The concentration of the intact HSC/HPC chemo-attractant, CXCL12, was greater in splenic MF plasma than PB MF plasma as quantified using mass spectrometry. Functionally inactive truncated products of CXCL12 which are the product of proteolytic degradation by serine proteases were detected at similar levels in both splenic and PB MF plasma. Treatment with an anti-CXCL12 neutralizing antibody resulted in a reduction in the degree of migration of splenic MF CD34+ cells towards both PB and splenic MF plasma validating the role of CXCL12 as a functional chemo-attractant. Our data indicate that the MF splenic microenvironment is characterized by increased levels of intact, functional CXCL12, which contributes to the localization of MF CD34+ cells to the spleen and the establishment of EMH. PMID:25461253

  10. Tie2 Expressing Monocytes in the Spleen of Patients with Primary Myelofibrosis.

    PubMed

    Campanelli, Rita; Fois, Gabriela; Catarsi, Paolo; Poletto, Valentina; Villani, Laura; Erba, Benedetta Gaia; Maddaluno, Luigi; Jemos, Basilio; Salmoiraghi, Silvia; Guglielmelli, Paola; Abbonante, Vittorio; Di Buduo, Christian Andrea; Balduini, Alessandra; Iurlo, Alessandra; Barosi, Giovanni; Rosti, Vittorio; Massa, Margherita

    2016-01-01

    Primary myelofibrosis (PMF) is a Philadelphia-negative (Ph-) myeloproliferative disorder, showing abnormal CD34+ progenitor cell trafficking, splenomegaly, marrow fibrosis leading to extensive extramedullary haematopoiesis, and abnormal neoangiogenesis in either the bone marrow or the spleen. Monocytes expressing the angiopoietin-2 receptor (Tie2) have been shown to support abnormal angiogenic processes in solid tumors through a paracrine action that takes place in proximity to the vessels. In this study we investigated the frequency of Tie2 expressing monocytes in the spleen tissue samples of patients with PMF, and healthy subjects (CTRLs), and evaluated their possible role in favouring spleen angiogenesis. We show by confocal microscopy that in the spleen tissue of patients with PMF, but not of CTRLs, the most of the CD14+ cells are Tie2+ and are close to vessels; by flow cytometry, we found that Tie2 expressing monocytes were Tie2+CD14lowCD16brightCDL62-CCR2- (TEMs) and their frequency was higher (p = 0.008) in spleen tissue-derived mononuclear cells (MNCs) of patients with PMF than in spleen tissue-derived MNCs from CTRLs undergoing splenectomy for abdominal trauma. By in vitro angiogenesis assay we evidenced that conditioned medium of immunomagnetically selected spleen tissue derived CD14+ cells of patients with PMF induced a denser tube like net than that of CTRLs; in addition, CD14+Tie2+ cells sorted from spleen tissue derived single cell suspension of patients with PMF show a higher expression of genes involved in angiogenesis than that found in CTRLs. Our results document the enrichment of Tie2+ monocytes expressing angiogenic genes in the spleen of patients with PMF, suggesting a role for these cells in starting/maintaining the pathological angiogenesis in this organ. PMID:27281335

  11. Endogenous retrovirus induces leukemia in a xenograft mouse model for primary myelofibrosis

    PubMed Central

    Triviai, Ioanna; Ziegler, Marion; Bergholz, Ulla; Oler, Andrew J.; Stübig, Thomas; Prassolov, Vladimir; Fehse, Boris; Kozak, Christine A.; Kröger, Nicolaus; Stocking, Carol

    2014-01-01

    The compound immunodeficiencies in nonobese diabetic (NOD) inbred mice homozygous for the Prkdcscid and Il2rgnull alleles (NSG mice) permit engraftment of a wide-range of primary human cells, enabling sophisticated modeling of human disease. In studies designed to define neoplastic stem cells of primary myelofibrosis (PMF), a myeloproliferative neoplasm characterized by profound disruption of the hematopoietic microenvironment, we observed a high frequency of acute myeloid leukemia (AML) in NSG mice. AML was of mouse origin, confined to PMF-xenografted mice, and contained multiple clonal integrations of ecotropic murine leukemia virus (E-MuLV). Significantly, MuLV replication was not only observed in diseased mice, but also in nontreated NSG controls. Furthermore, in addition to the single ecotropic endogenous retrovirus (eERV) located on chromosome 11 (Emv30) in the NOD genome, multiple de novo germ-line eERV integrations were observed in mice from each of four independent NSG mouse colonies. Analysis confirmed that E-MuLV originated from the Emv30 provirus and that recombination events were not necessary for virus replication or AML induction. Pathogenicity is thus likely attributable to PMF-mediated paracrine stimulation of mouse myeloid cells, which serve as targets for retroviral infection and transformation, as evidenced by integration into the Evi1 locus, a hotspot for retroviral-induced myeloid leukemia. This study thus corroborates a role of paracrine stimulation in PMF disease progression, underlines the importance of target cell type and numbers in MuLV-induced disease, and mandates awareness of replicating MuLV in NOD immunodeficient mice, which can significantly influence experimental results and their interpretation. PMID:24912157

  12. The role of growth differentiation factor 15 in the pathogenesis of primary myelofibrosis

    PubMed Central

    Uchiyama, Tatsuki; Kawabata, Hiroshi; Miura, Yasuo; Yoshioka, Satoshi; Iwasa, Masaki; Yao, Hisayuki; Sakamoto, Soichiro; Fujimoto, Masakazu; Haga, Hironori; Kadowaki, Norimitsu; Maekawa, Taira; Takaori-Kondo, Akifumi

    2015-01-01

    Growth differentiation factor 15 (GDF15) is a pleiotropic cytokine that belongs to the transforming growth factor-β superfamily. Elevated serum concentrations of this cytokine have been reported in patients with various malignancies. To assess the potential roles of GDF15 in hematologic malignancies, we measured its serum levels in patients with these diseases. We found that serum GDF15 levels were elevated in almost all these patients, particularly in patients with primary myelofibrosis (PMF). Immunohistochemical staining of bone marrow (BM) specimens revealed that GDF15 was strongly expressed by megakaryocytes, which may be sources of increased serum GDF15 in PMF patients. Therefore, we further assessed the contribution of GDF15 to the pathogenesis of PMF. Recombinant human (rh) GDF15 enhanced the growth of human BM mesenchymal stromal cells (BM-MSCs), and it enhanced the potential of these cells to support human hematopoietic progenitor cell growth in a co-culture system. rhGDF15 enhanced the growth of human primary fibroblasts, but it did not affect their expression of profibrotic genes. rhGDF15 induced osteoblastic differentiation of BM-MSCs in vitro, and pretreatment of BM-MSCs with rGDF15 enhanced the induction of bone formation in a xenograft mouse model. These results suggest that serum levels of GDF15 in PMF are elevated, that megakaryocytes are sources of this cytokine in BM, and that GDF15 may modulate the pathogenesis of PMF by enhancing proliferation and promoting osteogenic differentiation of BM-MSCs. PMID:26276681

  13. Characterization of the TGF-β1 signaling abnormalities in the Gata1low mouse model of myelofibrosis

    PubMed Central

    Zingariello, Maria; Martelli, Fabrizio; Ciaffoni, Fiorella; Masiello, Francesca; Ghinassi, Barbara; D’Amore, Emanuela; Massa, Margherita; Barosi, Giovanni; Sancillo, Laura; Li, Xiaochun; Goldberg, Judith D.; Rana, Rosa Alba

    2013-01-01

    Primary myelofibrosis (PMF) is characterized by fibrosis, ineffective hematopoiesis in marrow, and hematopoiesis in extramedullary sites and is associated with abnormal megakaryocyte (MK) development and increased transforming growth factor (TGF)-β1 release. To clarify the role of TGF-β1 in the pathogenesis of this disease, the TGF-β1 signaling pathway of marrow and spleen of the Gata1low mouse model of myelofibrosis (MF) was profiled and the consequences of inhibition of TGF-β1 signaling on disease manifestations determined. The expression of 20 genes in marrow and 36 genes in spleen of Gata1low mice was altered. David-pathway analyses identified alterations of TGF-β1, Hedgehog, and p53 signaling in marrow and spleen and of mammalian target of rapamycin (mTOR) in spleen only and predicted that these alterations would induce consequences consistent with the Gata1low phenotype (increased apoptosis and G1 arrest both in marrow and spleen and increased osteoblast differentiation and reduced ubiquitin-mediated proteolysis in marrow only). Inhibition of TGF-β1 signaling normalized the expression of p53-related genes, restoring hematopoiesis and MK development and reducing fibrosis, neovascularization, and osteogenesis in marrow. It also normalized p53/mTOR/Hedgehog-related genes in spleen, reducing extramedullary hematopoiesis. These data identify altered expression signatures of TGF-β1 signaling that may be responsible for MF in Gata1low mice and may represent additional targets for therapeutic intervention in PMF. PMID:23462118

  14. Expression of the TEL-Syk Fusion Protein in Hematopoietic Stem Cells Leads to Rapidly Fatal Myelofibrosis in Mice

    PubMed Central

    Graham, Michelle T.; Abram, Clare L.; Hu, Yongmei; Lowell, Clifford A.

    2013-01-01

    The TEL-Syk fusion protein was isolated from a patient with myelodysplasia with megakaryocyte blasts. Expression of TEL-Syk transforms interleukin-3 (IL-3)-dependent Ba/F3 cells in vitro by deregulating STAT5-mediated signal transduction pathways. In vivo, TEL-Syk expression in pre-B cells blocks B cell differentiation, leading to lymphoid leukemia. Here, we demonstrate that TEL-Syk introduced into fetal liver hematopoietic cells, which are then adoptively transferred into lethally irradiated recipients, leads to an aggressive myelodysplasia with myelofibrosis that is lethal in mice by 60–75 days. Expression of TEL-Syk induces a short-lived myeloexpansion that is rapidly followed by bone marrow failure and extreme splenic/hepatic fibrosis accompanied by extensive apoptosis. The disease is dependent on Syk kinase activity. Analysis of serum from TEL-Syk mice reveals an inflammatory cytokine signature reminiscent of that found in the sera from patients and mouse models of myeloproliferative neoplasms. TEL-Syk expressing cells showed constitutive STAT5 phosphorylation, which was resistant to JAK inhibition, consistent with deregulated cytokine signaling. These data indicate that expression of TEL-Syk in fetal liver hematopoietic cells results in JAK-independent STAT5 phosphorylation ultimately leading to a uniquely aggressive and lethal form of myelofibrosis. PMID:24116232

  15. Rapidly progressed aortic stenosis in a patient with previous diagnosis of polycythemia vera and post-polycythemia vera myelofibrosis.

    PubMed

    Kiso, Shohei; Naito, Ryo; Fukao, Kosuke; Hiki, Makoto; Miyazaki, Tetsuro; Takagi, Atsutoshi; Miyauchi, Katsumi; Daida, Hiroyuki

    2016-06-01

    Polycythemia vera (PV) is a chronic myeloproliferative disease that is often complicated with thromboembolism. However, aortic stenosis (AS) could be a manifestation of the cardiovascular complications of PV possibly through shear stress and atherosclerosis. We report a rare case of rapidly progressed AS in a patient with PV. PMID:27398203

  16. Effect of Ruxolitinib Therapy on Myelofibrosis-Related Symptoms and Other Patient-Reported Outcomes in COMFORT-I: A Randomized, Double-Blind, Placebo-Controlled Trial

    PubMed Central

    Mesa, Ruben A.; Gotlib, Jason; Gupta, Vikas; Catalano, John V.; Deininger, Michael W.; Shields, Alan L.; Miller, Carole B.; Silver, Richard T.; Talpaz, Moshe; Winton, Elliott F.; Harvey, Jimmie H.; Hare, Thomas; Erickson-Viitanen, Susan; Sun, William; Sandor, Victor; Levy, Richard S.; Kantarjian, Hagop M.; Verstovsek, Srdan

    2013-01-01

    Purpose To assess the effects of ruxolitinib on symptom burden and quality of life (QoL) and to evaluate the ability of the modified Myelofibrosis Symptom Assessment Form (MFSAF) v2.0 to measure meaningful changes in myelofibrosis-related symptoms in patients with myelofibrosis. Patients and Methods COMFORT-I (Controlled Myelofibrosis Study With Oral JAK Inhibitor Treatment–I) is a double-blind, placebo-controlled phase III study evaluating ruxolitinib in patients with intermediate-2 or high-risk myelofibrosis. Exploratory analyses were conducted on the following patient-reported outcomes (PROs) assessments: modified MFSAF v2.0 (individual symptoms and Total Symptom Score [TSS]), European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue Scale, and Patient Global Impression of Change (PGIC). Results Patients receiving ruxolitinib experienced improvements in individual myelofibrosis-related symptoms, although patients receiving placebo experienced worsening (P < .001). The majority (91%) of ruxolitinib-treated patients designated as ≥ 50% TSS responders (≥ 50% TSS improvement) self-reported their condition as either “Much improved” or “Very much improved” on the PGIC. These patients achieved significant improvements in the EORTC QLQ-C30 functional domains and Global Health Status/QoL versus patients receiving placebo, who experienced worsening on these measures (P ≤ .0135). Ruxolitinib-treated patients with a lesser degree of symptom improvement (< 50% TSS responders) also achieved improvements over placebo on these measures. The degree of spleen volume reduction with ruxolitinib correlated with improvements in TSS, PGIC, PROMIS Fatigue Scale, and EORTC Global Health Status/QoL. Ruxolitinib-treated patients who achieved a ≥ 35% reduction in spleen volume experienced the greatest improvements in these PROs. Conclusion

  17. Sclerosing extramedullary hematopoietic tumor presenting as an inguinal mass in a patient with primary myelofibrosis: a diagnostic pitfall

    PubMed Central

    Gu, Mi-Jin

    2015-01-01

    Sclerosing extramedullary hematopoietic tumor (SEMHT) is a rare lesion and presented as retroperitoneal or serosal-based mass. A 53-year-old man with a long history of primary myelofibrosis, presented with abdominal distension and inguinal mass. Pathologic examination of inguinal mass revealed a prominent sclerotic background with thick collagen deposits and mono, bi, or tri-lineage hematopoietic tissue containing atypical megakaryocytes and variable proportions of myeloid and erythroid series. The atypical megakaryocytes were positive for Factor VIII and CD61. SEMHT may be misdiagnosed as lymphocyte depleted Hodgkin’s disease, as a mesenchymal neoplasm, or as carcinoma, because of the presence of large atypical cells and marked fibrosis when clinical information regarding PMF is unknown. Awareness of the bizarre atypical megakaryocyte morphology with immature hematopoietic cells and of clinical history is essential to prevent misdiagnosis. PMID:26045874

  18. Frequency of Calreticulin (CALR) Mutation and Its Clinical Prognostic Significance in Essential Thrombocythemia and Primary Myelofibrosis: A Meta-analysis.

    PubMed

    Kong, Hao; Liu, Yancheng; Luo, Sai; Li, Qiaoqiao; Wang, Qinglu

    2016-01-01

    Objective As the calreticulin (CALR) mutation frequency is significantly associated with essential thrombocythemia (ET) and primary myelofibrosis (PMF), this mutation may be an important biomarker in patients with ET and PMF. Methods We performed a literature search until April 2015 and obtained 21 relevant studies. The outcome was pooled as the effect size by using the Stata software program. Results The CALR mutation frequencies in patients with ET and PMF were 19% and 22%, respectively. The CALR mutation ratio in Asian patients with ET was 23% and higher than that in European-American patients (16%). Moreover, the mutation ratio in Asian patients with PMF was lower (21%) than that in European-American patients (23%). A slight trend toward fibrotic transformation was found in ET with CALR mutations, whereas leukemic transformation was not significant in patients with ET or PMF with CALR mutations. Conclusion CALR mutations significantly influence the incident of ET as demonstrated by the meta-analysis. PMID:27477402

  19. Relationship between the 46/1 haplotype of the JAK2 gene and the JAK2 mutational status and allele burden, the initial findings, and the survival of patients with myelofibrosis.

    PubMed

    Martínez-Trillos, Alejandra; Maffioli, Margherita; Colomer, Dolors; Alvarez-Larrán, Alberto; Pereira, Arturo; Angona, Anna; Bellosillo, Beatriz; Cervantes, Francisco

    2014-05-01

    An association has been reported between a specific haplotype of the JAK2 gene, the homozygous 46/1 haplotype, and a predisposition to the development of chromosome Philadelphia-negative myeloproliferative neoplasms. Concerning myelofibrosis (MF), controversy remains on the relationship between the above JAK2 haplotype and the patients' clinicohematological features and survival. Among 132 patients with MF (60 % primary MF, 20 % postpolycythemia vera MF, 20 % post-essential thrombocythemia MF; 59 % JAK2V617F positive) who were analyzed for the JAK2 46/1 haplotype, 29 were found to be homozygous and 53 heterozygous. The homozygous 46/1 haplotype was more often observed in JAK2V617F-positive patients (29.5 versus 11 %, p = 0.012). Moreover, among JAK2V617F-positive patients, those who were homozygous for the 46/1 haplotype had a higher allele burden than the remainder (92 versus 48 %, p = 0.0017). Overall, patients with homozygous 46/1 haplotype showed significantly higher hemoglobin values and higher leukocyte counts, but no association was seen with other clinicohematological features. Finally, no relationship was observed between the JAK2 46/1 haplotype and either the patients' prognostic score or survival. PMID:24337516

  20. Long-term findings from COMFORT-II, a phase 3 study of ruxolitinib vs best available therapy for myelofibrosis.

    PubMed

    Harrison, C N; Vannucchi, A M; Kiladjian, J-J; Al-Ali, H K; Gisslinger, H; Knoops, L; Cervantes, F; Jones, M M; Sun, K; McQuitty, M; Stalbovskaya, V; Gopalakrishna, P; Barbui, T

    2016-08-01

    Ruxolitinib is a Janus kinase (JAK) (JAK1/JAK2) inhibitor that has demonstrated superiority over placebo and best available therapy (BAT) in the Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment (COMFORT) studies. COMFORT-II was a randomized (2:1), open-label phase 3 study in patients with myelofibrosis; patients randomized to BAT could crossover to ruxolitinib upon protocol-defined disease progression or after the primary end point, confounding long-term comparisons. At week 48, 28% (41/146) of patients randomized to ruxolitinib achieved ⩾35% decrease in spleen volume (primary end point) compared with no patients on BAT (P<0.001). Among the 78 patients (53.4%) in the ruxolitinib arm who achieved ⩾35% reductions in spleen volume at any time, the probability of maintaining response was 0.48 (95% confidence interval (CI), 0.35-0.60) at 5 years (median, 3.2 years). Median overall survival was not reached in the ruxolitinib arm and was 4.1 years in the BAT arm. There was a 33% reduction in risk of death with ruxolitinib compared with BAT by intent-to-treat analysis (hazard ratio (HR)=0.67; 95% CI, 0.44-1.02; P=0.06); the crossover-corrected HR was 0.44 (95% CI, 0.18-1.04; P=0.06). There was no unexpected increased incidence of adverse events with longer exposure. This final analysis showed that spleen volume reductions with ruxolitinib were maintained with continued therapy and may be associated with survival benefits. PMID:27211272

  1. Mutations and long-term outcome of 217 young patients with essential thrombocythemia or early primary myelofibrosis.

    PubMed

    Palandri, F; Latagliata, R; Polverelli, N; Tieghi, A; Crugnola, M; Martino, B; Perricone, M; Breccia, M; Ottaviani, E; Testoni, N; Merli, F; Aversa, F; Alimena, G; Cavo, M; Martinelli, G; Catani, L; Baccarani, M; Vianelli, N

    2015-06-01

    We investigated the influence of molecular status on disease characteristics and clinical outcome in young patients (⩽ 40 years) with World Health Organization (WHO)-defined essential thrombocythemia (ET) or early/prefibrotic primary myelofibrosis (early-PMF). Overall, 217 patients with ET (number 197) and early-PMF (number 20) were included in the analysis. Median follow-up time was 10.2 years. The cumulative incidence of thrombosis, hemorrhages and disease evolution into myelofibrosis/acute leukemia were 16.6%, 8.6% and 3% at 15 years, respectively. No differences were detectable between ET and early-PMF patients, although the latter cohort showed a trend for worse combined-event free survival (EFS). Mutation frequency were 61% for JAK2V617F, 25% for CALR and 1% for MPLW515K, and were comparable across WHO diagnosis; however, JAK2V617F allele burden was higher in the early-PMF group. Compared with JAK2V617F-positive patients, CALR-mutated patients displayed higher platelet count and lower hemoglobin level. CALR mutations significantly correlated with lower thrombotic risk (9.1% versus 21.7%, P = 0.04), longer survival (100% versus 96%, P = 0.05) and better combined-EFS (86% versus 71%, P = 0.02). However, non-type 1/type 2 CALR mutations ('minor' mutations) and abnormal karyotype were found to correlate with increased risk of disease evolution. At last contact, six patients had died; in five cases, the causes of death were related to the hematological disease and occurred at a median age of 64 years (range: 53-68 years). Twenty-eight patients (13%) were unmutated for JAK2, CALR and MPL: no event was registered in these 'triple-negative' patients. PMID:25801912

  2. A dominant gain-of-function mutation in universal tyrosine kinase SRC causes thrombocytopenia, myelofibrosis, bleeding, and bone pathologies.

    PubMed

    Turro, Ernest; Greene, Daniel; Wijgaerts, Anouck; Thys, Chantal; Lentaigne, Claire; Bariana, Tadbir K; Westbury, Sarah K; Kelly, Anne M; Selleslag, Dominik; Stephens, Jonathan C; Papadia, Sofia; Simeoni, Ilenia; Penkett, Christopher J; Ashford, Sofie; Attwood, Antony; Austin, Steve; Bakchoul, Tamam; Collins, Peter; Deevi, Sri V V; Favier, Rémi; Kostadima, Myrto; Lambert, Michele P; Mathias, Mary; Millar, Carolyn M; Peerlinck, Kathelijne; Perry, David J; Schulman, Sol; Whitehorn, Deborah; Wittevrongel, Christine; De Maeyer, Marc; Rendon, Augusto; Gomez, Keith; Erber, Wendy N; Mumford, Andrew D; Nurden, Paquita; Stirrups, Kathleen; Bradley, John R; Lucy Raymond, F; Laffan, Michael A; Van Geet, Chris; Richardson, Sylvia; Freson, Kathleen; Ouwehand, Willem H

    2016-03-01

    The Src family kinase (SFK) member SRC is a major target in drug development because it is activated in many human cancers, yet deleterious SRC germline mutations have not been reported. We used genome sequencing and Human Phenotype Ontology patient coding to identify a gain-of-function mutation in SRC causing thrombocytopenia, myelofibrosis, bleeding, and bone pathologies in nine cases. Modeling of the E527K substitution predicts loss of SRC's self-inhibitory capacity, which we confirmed with in vitro studies showing increased SRC kinase activity and enhanced Tyr(419) phosphorylation in COS-7 cells overexpressing E527K SRC. The active form of SRC predominates in patients' platelets, resulting in enhanced overall tyrosine phosphorylation. Patients with myelofibrosis have hypercellular bone marrow with trilineage dysplasia, and their stem cells grown in vitro form more myeloid and megakaryocyte (MK) colonies than control cells. These MKs generate platelets that are dysmorphic, low in number, highly variable in size, and have a paucity of α-granules. Overactive SRC in patient-derived MKs causes a reduction in proplatelet formation, which can be rescued by SRC kinase inhibition. Stem cells transduced with lentiviral E527K SRC form MKs with a similar defect and enhanced tyrosine phosphorylation levels. Patient-derived and E527K-transduced MKs show Y419 SRC-positive stained podosomes that induce altered actin organization. Expression of mutated src in zebrafish recapitulates patients' blood and bone phenotypes. Similar studies of platelets and MKs may reveal the mechanism underlying the severe bleeding frequently observed in cancer patients treated with next-generation SFK inhibitors. PMID:26936507

  3. Small RNA Sequencing Uncovers New miRNAs and moRNAs Differentially Expressed in Normal and Primary Myelofibrosis CD34+ Cells

    PubMed Central

    Saccoman, Claudia; Mannarelli, Carmela; Coppe, Alessandro; Vannucchi, Alessandro M.; Bortoluzzi, Stefania

    2015-01-01

    Myeloproliferative neoplasms (MPN) are chronic myeloid cancers thought to arise at the level of CD34+ hematopoietic stem/progenitor cells. They include essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (PMF). All can progress to acute leukemia, but PMF carries the worst prognosis. Increasing evidences indicate that deregulation of microRNAs (miRNAs) might plays an important role in hematologic malignancies, including MPN. To attain deeper knowledge of short RNAs (sRNAs) expression pattern in CD34+ cells and of their possible role in mediating post-transcriptional regulation in PMF, we sequenced with Illumina HiSeq2000 technology CD34+ cells from healthy subjects and PMF patients. We detected the expression of 784 known miRNAs, with a prevalence of miRNA up-regulation in PMF samples, and discovered 34 new miRNAs and 99 new miRNA-offset RNAs (moRNAs), in CD34+ cells. Thirty-seven small RNAs were differentially expressed in PMF patients compared with healthy subjects, according to microRNA sequencing data. Five miRNAs (miR-10b-5p, miR-19b-3p, miR-29a-3p, miR-379-5p, and miR-543) were deregulated also in PMF granulocytes. Moreover, 3’-moR-128-2 resulted consistently downregulated in PMF according to RNA-seq and qRT-PCR data both in CD34+ cells and granulocytes. Target predictions of these validated small RNAs de-regulated in PMF and functional enrichment analyses highlighted many interesting pathways involved in tumor development and progression, such as signaling by FGFR and DAP12 and Oncogene Induced Senescence. As a whole, data obtained in this study deepened the knowledge of miRNAs and moRNAs altered expression in PMF CD34+ cells and allowed to identify and validate a specific small RNA profile that distinguishes PMF granulocytes from those of normal subjects. We thus provided new information regarding the possible role of miRNAs and, specifically, of new moRNAs in this disease. PMID:26468945

  4. Masked polycythemia vera (mPV): results of an international study.

    PubMed

    Barbui, Tiziano; Thiele, Jürgen; Gisslinger, Heinz; Finazzi, Guido; Carobbio, Alessandra; Rumi, Elisa; Luigia Randi, Maria; Betozzi, Irene; Vannucchi, Alessandro M; Pieri, Lisa; Carrai, Valentina; Gisslinger, Bettina; Müllauer, Leonhard; Ruggeri, Marco; Rambaldi, Alessandro; Tefferi, Ayalew

    2014-01-01

    We examined the baseline features and clinical outcomes of 140 patients presenting with JAK2V617F positivity and a bone marrow morphology conforming with WHO criteria of polycythemia vera (PV), but a hemoglobin level of <18.5 g/dL in males (range 16.0-18.4) and <16.5 g/dL in females (range 15.0-16.4). This cohort operationally referred to as masked PV (mPV) was compared with 257 patients with overt PV and displayed male predominance, a more frequent history of arterial thrombosis and thrombocytosis. Incidence of thrombosis was similar between the two groups but mPV displayed significantly higher rates of progression to myelofibrosis and acute leukemia and inferior survival. In multivariable analysis mPV diagnosis was an independent predictor of poor survival along with age >65 years and leukocyte count >10 × 10(9) /L. Our data suggest that mPV is a heterogeneous myeloproliferative neoplasia and not necessarily an early/ pre-polycythemic form of classical PV that at onset in a small fraction of patients clinically may mimic essential thrombocythemia. On the other hand, the majority mPV may have a longer prodrome of undiagnosed PV or a disease biology akin to primary myelofibrosis-post PV myelofibrosis that could explain the worsening of outcome in comparison to overt/classical manifestations. PMID:23996471

  5. Comprehensive whole-genome sequencing of an early-stage primary myelofibrosis patient defines low mutational burden and non-recurrent candidate genes.

    PubMed

    Merker, Jason D; Roskin, Krishna M; Ng, Dana; Pan, Cuiping; Fisk, Dianna G; King, Jasmine J; Hoh, Ramona; Stadler, Michael; Okumoto, Lawrence M; Abidi, Parveen; Hewitt, Rhonda; Jones, Carol D; Gojenola, Linda; Clark, Michael J; Zhang, Bing; Cherry, Athena M; George, Tracy I; Snyder, Michael; Boyd, Scott D; Zehnder, James L; Fire, Andrew Z; Gotlib, Jason

    2013-11-01

    In order to identify novel somatic mutations associated with classic BCR/ABL1-negative myeloproliferative neoplasms, we performed high-coverage genome sequencing of DNA from peripheral blood granulocytes and cultured skin fibroblasts from a patient with MPL W515K-positive primary myelofibrosis. The primary myelofibrosis genome had a low somatic mutation rate, consistent with that observed in similar hematopoietic tumor genomes. Interfacing of whole-genome DNA sequence data with RNA expression data identified three somatic mutations of potential functional significance: i) a nonsense mutation in CARD6, implicated in modulation of NF-kappaB activation; ii) a 19-base pair deletion involving a potential regulatory region in the 5'-untranslated region of BRD2, implicated in transcriptional regulation and cell cycle control; and iii) a non-synonymous point mutation in KIAA0355, an uncharacterized protein. Additional mutations in three genes (CAP2, SOX30, and MFRP) were also evident, albeit with no support for expression at the RNA level. Re-sequencing of these six genes in 178 patients with polycythemia vera, essential thrombocythemia, and myelofibrosis did not identify recurrent somatic mutations in these genes. Finally, we describe methods for reducing false-positive variant calls in the analysis of hematologic malignancies with a low somatic mutation rate. This trial is registered with ClinicalTrials.gov (NCT01108159). PMID:23872309

  6. Myeloproliferative neoplasms working group consensus recommendations for diagnosis and management of primary myelofibrosis, polycythemia vera, and essential thrombocythemia

    PubMed Central

    Agarwal, M. B.; Malhotra, Hemant; Chakrabarti, Prantar; Varma, Neelam; Mathews, Vikram; Bhattacharyya, Jina; Seth, Tulika; Gayathri, K.; Menon, Hari; Subramanian, P. G.; Sharma, Ajay; Bhattacharyya, Maitreyee; Mehta, Jay; Vaid, A. K.; Shah, Sandeep; Aggarwal, Shyam; Gogoi, P. K.; Nair, Reena; Agarwal, Usha; Varma, Subhash; Prasad, S. V. S. S.; Manipadam, Marie Therese

    2015-01-01

    According to the 2008 revision of the World Health Organization (WHO) classification of myeloid malignancies, philadelphia chromosome (Ph)-negative myeloproliferative neoplasms (MPNs) include clonal, hematologic disorders such as polycythemia vera, primary myelofibrosis, and essential thrombocythemia.Recent years have witnessed major advances in the understanding of the molecular pathophysiology of these rare subgroups of chronic, myeloproliferative disorders. Identification of somatic mutations in genes associated with pathogenesis and evolution of these myeloproliferative conditions (Janus Kinase 2; myeloproliferative leukemia virus gene; calreticulin) led to substantial changes in the international guidelines for diagnosis and treatment of Ph-negative MPN during the last few years.The MPN-Working Group (MPN-WG), a panel of hematologists with expertise in MPN diagnosis and treatment from various parts of India, examined applicability of this latest clinical and scientific evidence in the context of hematology practice in India.This manuscript summarizes the consensus recommendations formulated by the MPN-WG that can be followed as a guideline for management of patients with Ph-negative MPN in the context of clinical practice in India. PMID:25810569

  7. Clonal Evolution Revealed by Whole Genome Sequencing in a Case of Primary Myelofibrosis Transformed to Secondary Acute Myeloid Leukemia

    PubMed Central

    Engle, Elizabeth K.; Fisher, Daniel A.C.; Miller, Christopher A.; McLellan, Michael D.; Fulton, Robert S.; Moore, Deborah M.; Wilson, Richard K.; Ley, Timothy J.; Oh, Stephen T.

    2014-01-01

    Clonal architecture in myeloproliferative neoplasms (MPNs) is poorly understood. Here we report genomic analyses of a patient with primary myelofibrosis (PMF) transformed to secondary acute myeloid leukemia (sAML). Whole genome sequencing (WGS) was performed on PMF and sAML diagnosis samples, with skin included as a germline surrogate. Deep sequencing validation was performed on the WGS samples and an additional sample obtained during sAML remission/relapsed PMF. Clustering analysis of 649 validated somatic single nucleotide variants revealed four distinct clonal groups, each including putative driver mutations. The first group (including JAK2 and U2AF1), representing the founding clone, included mutations with high frequency at all three disease stages. The second clonal group (including MYB) was present only in PMF, suggesting the presence of a clone that was dispensable for transformation. The third group (including ASXL1) contained mutations with low frequency in PMF and high frequency in subsequent samples, indicating evolution of the dominant clone with disease progression. The fourth clonal group (including IDH1 and RUNX1) was acquired at sAML transformation and was predominantly absent at sAML remission/relapsed PMF. Taken together, these findings illustrate the complex clonal dynamics associated with disease evolution in MPNs and sAML. PMID:25252869

  8. Hematopoietic Cell Transplantation as Curative Therapy for Patients with Myelofibrosis: Long-Term Success in all Age Groups.

    PubMed

    Deeg, H Joachim; Bredeson, Christopher; Farnia, Stephanie; Ballen, Karen; Gupta, Vikas; Mesa, Ruben A; Popat, Uday; Hari, Parameswaran; Saber, Wael; Seftel, Matthew; Tamari, Roni; W Petersdorf, Effie

    2015-11-01

    Myeloproliferative neoplasms (MPN) are chronic marrow disorders with variable prognoses. Most patients with polycythemia vera, essential thrombocythemia, or even primary myelofibrosis (PMF) are successfully treated with conservative strategies for years or even decades, and recent data suggest that even in patients with high-risk disease, in particular those with PMF, life expectancy can be extended by treatment with janus kinase (JAK2) inhibitors. However, none of those modalities are curative, and after marrow failure develops, the disease "accelerates," or transforms to acute leukemia, the only option able to effectively treat and, in fact, cure MPN is allogeneic hematopoietic cell transplantation (HCT). Outcome is superior if HCT is performed before leukemic transformation occurs. Several reports document survival in unmaintained remission beyond 10 years. The most recent analyses show reduced regimen-related mortality (less than 10% or even 5% at day 100) and progressively improved survival with both HLA-identical sibling and unrelated donors. The development of low/reduced-intensity conditioning regimens has contributed to the improved success rate and has allowed successful HCT in patients in their seventh and even eighth decade of life. We propose, therefore, that HCT should be offered to fit patients in these age groups and should be covered by their respective insurance carriers. PMID:26371371

  9. Hemoglobin levels and circulating blasts are two easily evaluable diagnostic parameters highly predictive of leukemic transformation in primary myelofibrosis.

    PubMed

    Rago, Angela; Latagliata, Roberto; Montanaro, Marco; Montefusco, Enrico; Andriani, Alessandro; Crescenzi, Sabrina Leonetti; Mecarocci, Sergio; Spirito, Francesca; Spadea, Antonio; Recine, Umberto; Cicconi, Laura; Avvisati, Giuseppe; Cedrone, Michele; Breccia, Massimo; Porrini, Raffaele; Villivà, Nicoletta; De Gregoris, Cinzia; Alimena, Giuliana; D'Arcangelo, Enzo; Guglielmelli, Paola; Lo-Coco, Francesco; Vannucchi, Alessandro; Cimino, Giuseppe

    2015-03-01

    To predict leukemic transformation (LT), we evaluated easily detectable diagnostic parameters in 338 patients with primary myelofibrosis (PMF) followed in the Latium region (Italy) between 1981 and 2010. Forty patients (11.8%) progressed to leukemia, with a resulting 10-year leukemia-free survival (LFS) rates of 72%. Hb (<10g/dL), and circulating blasts (≥1%) were the only two independent prognostic for LT at the multivariate analysis. Two hundred-fifty patients with both the two parameters available were grouped as follows: low risk (none or one factor)=216 patients; high risk (both factors)=31 patients. The median LFS times were 269 and 45 months for the low and high-risk groups, respectively (P<.0001). The LT predictive power of these two parameters was confirmed in an external series of 270 PMF patients from Tuscany, in whom the median LFS was not reached and 61 months for the low and high risk groups, respectively (P<.0001). These results establish anemia and circulating blasts, two easily and universally available parameters, as strong predictors of LT in PMF and may help to improve prognostic stratification of these patients particularly in countries with low resources where more sophisticated molecular testing is unavailable. PMID:25636356

  10. Prognostic impact of bone marrow fibrosis in primary myelofibrosis. A study of the AGIMM group on 490 patients.

    PubMed

    Guglielmelli, Paola; Rotunno, Giada; Pacilli, Annalisa; Rumi, Elisa; Rosti, Vittorio; Delaini, Federica; Maffioli, Margherita; Fanelli, Tiziana; Pancrazzi, Alessandro; Pieri, Lisa; Fjerza, Rajmonda; Pietra, Daniela; Cilloni, Daniela; Sant'Antonio, Emanuela; Salmoiraghi, Silvia; Passamonti, Francesco; Rambaldi, Alessandro; Barosi, Giovanni; Barbui, Tiziano; Cazzola, Mario; Vannucchi, Alessandro M

    2016-09-01

    The prognostic significance of bone marrow (BM) fibrosis grade in patients with primary myelofibrosis (PMF) is still debated. A fibrosis grade greater than 1 was shown to associate with higher risk of death, and addition of fibrosis grade to IPSS score resulted in a more accurate prediction of survival. The aim of this study was to analyze the prognostic impact of BM fibrosis in 490 patients with PMF, evaluated at diagnosis, molecularly annotated and with extensive follow-up information. We found that fibrosis grade 2 and greater on a 0-3 scale was associated with clinical characteristics indicative of a more advanced disease, such as anemia, leukopenia, thrombocytopenia, constitutional symptoms, larger splenomegaly and a higher IPSS risk category. Patients with higher grade of fibrosis were also more likely to have additional somatic mutations in ASXL1 and EZH2, that are prognostically adverse. Median survival was significantly reduced in patients with grade 2 and 3 fibrosis as compared with grade 1; this effect was maintained when analysis was restricted to younger patients. In multivariate analysis, fibrosis grade independently predicted for survival regardless of IPSS variables and mutational status; the adverse impact of fibrosis was noticeable especially in lower IPSS risk categories. Overall, results indicate that higher grades of fibrosis correlate with unique clinical and molecular aspects and represent an independent adverse variable in patients with PMF; these observations deserve confirmation in prospectively designed series of patients. Am. J. Hematol. 91:918-922, 2016. © 2016 Wiley Periodicals, Inc. PMID:27264006

  11. Myeloproliferative neoplasms working group consensus recommendations for diagnosis and management of primary myelofibrosis, polycythemia vera, and essential thrombocythemia.

    PubMed

    Agarwal, M B; Malhotra, Hemant; Chakrabarti, Prantar; Varma, Neelam; Mathews, Vikram; Bhattacharyya, Jina; Seth, Tulika; Gayathri, K; Menon, Hari; Subramanian, P G; Sharma, Ajay; Bhattacharyya, Maitreyee; Mehta, Jay; Vaid, A K; Shah, Sandeep; Aggarwal, Shyam; Gogoi, P K; Nair, Reena; Agarwal, Usha; Varma, Subhash; Prasad, S V S S; Manipadam, Marie Therese

    2015-01-01

    According to the 2008 revision of the World Health Organization (WHO) classification of myeloid malignancies, philadelphia chromosome (Ph)-negative myeloproliferative neoplasms (MPNs) include clonal, hematologic disorders such as polycythemia vera, primary myelofibrosis, and essential thrombocythemia.Recent years have witnessed major advances in the understanding of the molecular pathophysiology of these rare subgroups of chronic, myeloproliferative disorders. Identification of somatic mutations in genes associated with pathogenesis and evolution of these myeloproliferative conditions (Janus Kinase 2; myeloproliferative leukemia virus gene; calreticulin) led to substantial changes in the international guidelines for diagnosis and treatment of Ph-negative MPN during the last few years.The MPN-Working Group (MPN-WG), a panel of hematologists with expertise in MPN diagnosis and treatment from various parts of India, examined applicability of this latest clinical and scientific evidence in the context of hematology practice in India.This manuscript summarizes the consensus recommendations formulated by the MPN-WG that can be followed as a guideline for management of patients with Ph-negative MPN in the context of clinical practice in India. PMID:25810569

  12. X-linked thrombocytopenia with thalassemia displays bone marrow reticulin fibrosis and enhanced angiogenesis: comparisons with primary myelofibrosis.

    PubMed

    Åström, Maria; Hahn-Strömberg, Victoria; Zetterberg, Eva; Vedin, Inger; Merup, Mats; Palmblad, Jan

    2015-03-01

    X-linked thrombocytopenia with thalassemia (XLTT) is caused by the mutation 216R > Q in exon 4 of the GATA1 gene. Male hemizygous patients display macrothrombocytopenia, splenomegaly, and a β-thalassemia trait. We describe two XLTT families where three males were initially misdiagnosed as having primary myelofibrosis (PMF) and all five investigated males showed mild-moderate bone marrow (BM) reticulin fibrosis. Comparative investigations were performed on blood samples and BM biopsies from males with XLTT, PMF patients and healthy controls. Like PMF, XLTT presented with high BM microvessel density, low GATA1 protein levels in megakaryocytes, and elevated blood CD34+ cell counts. But unlike PMF, the BM microvessel pericyte coverage was low in XLTT, and no collagen fibrosis was found. Further, as evaluated by immunohistochemistry, expressions of the growth factors VEGF, AGGF1, and CTGF were low in XLTT megakaryocytes and microvessels but high in PMF. Thus, although the reticulin fibrosis in XLTT might simulate PMF, opposing stromal and megakaryocyte features may facilitate differential diagnosis. Additional comparisons between these disorders may increase the understanding of mechanisms behind BM fibrosis in relation to pathological megakaryopoiesis. PMID:25421114

  13. Unraveling the genetic underpinnings of myeloproliferative neoplasms and understanding their effect on disease course and response to therapy: Proceedings from the 6th International Post-ASH Symposium

    PubMed Central

    Abdel-Wahab, Omar; Pardanani, Animesh; Bernard, Olivier; Finazzi, Guido; Crispino, John D.; Gisslinger, Heinz; Kralovics, Robert; Odenike, Olatoyosi; Bhalla, Kapil; Gupta, Vikas; Barosi, Giovanni; Gotlib, Jason; Guglielmelli, Paola; Kiladjian, Jean-Jacques; Noel, Pierre; Cazzola, Mario; Vannucchi, Alessandro M.; Hoffman, Ronald; Barbui, Tiziano; Thiele, Juergen; Van Etten, Richard A.; Mughal, Tariq I.; Tefferi, Ayalew

    2012-01-01

    Immediately after the annual scientific meeting of the American Society of Hematology (ASH), a select group of clinical and laboratory investigators in myeloproliferative neoplasms (MPN) is summoned to a post-ASH conference on chronic myeloid leukemia and the BCR-ABL1-negative MPN. The 6th such meeting occurred on 13th–14th December 2011, in La Jolla, California, USA, under the direction of its founder, Dr. Tariq Mughal. The current document is the first of two reports on this post-ASH event and summarizes the most recent preclinical and clinical advances in polycythemia vera, essential thrombocythemia and primary myelofibrosis. PMID:22460584

  14. Altered SDF-1/CXCR4 axis in patients with primary myelofibrosis and in the Gata1low mouse model of the disease

    PubMed Central

    Migliaccio, Anna Rita; Martelli, Fabrizio; Verrucci, Maria; Migliaccio, Giovanni; Vannucchi, Alessandro Maria; Ni, Hongyu; Xu, Mingjiang; Jiang, Yi; Nakamoto, Betty; Papayannopoulou, Thalia; Hoffman, Ronald

    2009-01-01

    Objective To assess whether alterations in the SDF-1/CXCR4 occur in patients with primary myelofibrosis (PMF) and in Gata1low mice, an animal model for myelofibrosis, and whether these abnormalities might account for increased stem/progenitor cell trafficking. Materials and Methods In the mouse, SDF-1 mRNA levels were assayed in liver, spleen and marrow. SDF-1 protein levels were quantified in plasma and marrow and CXCR4 mRNA and protein levels were evaluated on stem/progenitor cells and megakaryocytes purified from the marrow. SDF-1 protein levels were also evaluated in plasma and in marrow biopsy specimens obtained from normal donors and PMF patients. Results In Gata1low mice, the plasma SDF-1 protein was 5-times higher than normal in younger animals. Furthermore, SDF-1 immuno-staining of marrow sections progressively increased with age. Similar abnormalities were observed in PMF patients. In fact, the plasma SDF-1 levels in PMF patients were significantly higher (by 2-fold) than normal (p<0.01) and SDF-1 immuno-staining of marrow biopsiy specimens demonstrated increased SDF-1 deposition in specific areas. In two of the patients, SDF-1 deposition was normalized by curative therapy with allogenic stem cell transplantation. Similarly to what already has been reported for PMF patients, the marrow from Gata1low mice contained fewer CXCR4posCD117pos cells and these cells expressed low levels of CXCR4 mRNA and protein. Conclusion Similar abnormalities in the SDF-1/CXCR4 axis are observed in PMF patients and in the Gata1low mice model of myelofibrosis. We suggest that these abnormalities contribute to the increased stem/progenitor cell trafficking observed in this mouse model as well as patients with PMF. PMID:18206727

  15. A novel interaction between megakaryocytes and activated fibrocytes increases TGF-β bioavailability in the Gata1low mouse model of myelofibrosis

    PubMed Central

    Zingariello, Maria; Ruggeri, Alessandra; Martelli, Fabrizio; Marra, Manuela; Sancillo, Laura; Ceglia, Ilaria; Rana, Rosa Alba; Migliaccio, Anna Rita

    2015-01-01

    Despite numerous circumstantial evidences, the pathogenic role of TGF-β in primary myelofibrosis (PMF), the most severe of the Philadelphia-negative myeloproliferative neoplasms, is still unclear because of the modest (2-fold) increases in its plasma levels observed in PMF patients and in the Gata1low mouse model. Whether myelofibrosis is associated with increased bioavailability of TGF-β bound to fibrotic fibres is unknown. Transmission electron-microscopy (TEM) observations identified that spleen from PMF patients and Gata1low mice contained megakaryocytes with abnormally high levels of TGF-β and collagen fibres embedded in their cytoplasm. Additional immuno-TEM observations of spleen from Gata1low mice revealed the presence of numerous activated fibrocytes establishing with their protrusions a novel cellular interaction, defined as peripolesis, with megakaryocytes. These protrusions infiltrated the megakaryocyte cytoplasm releasing collagen that was eventually detected in its mature polymerized form. Megakaryocytes, engulfed with mature collagen fibres, acquired the morphology of para-apoptotic cells and, in the most advanced cases, were recognized as polylobated heterochromatic nuclei surrounded by collagen fibres strictly associated with TGF-β. These areas contained concentrations of TGF-β-gold particles ~1000-fold greater than normal and numerous myofibroblasts, an indication that TGF-β was bioactive. Loss-of-function studies indicated that peripolesis between megakaryocytes and fibrocytes required both TGF-β, possibly for inducing fibrocyte activation, and P-selectin, possibly for mediating interaction between the two cell types. Loss-of-function of TGF-β and P-selectin also prevented fibrosis. These observations identify that myelofibrosis is associated with pathological increases of TGF-β bioavailability and suggest a novel megakaryocyte-mediated mechanism that may increase TGF-β bioavailability in chronic inflammation. PMID:27069753

  16. Rationale for revision and proposed changes of the WHO diagnostic criteria for polycythemia vera, essential thrombocythemia and primary myelofibrosis

    PubMed Central

    Barbui, T; Thiele, J; Vannucchi, A M; Tefferi, A

    2015-01-01

    The 2001/2008 World Health Organization (WHO)-based diagnostic criteria for polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) were recently revised to accomodate new information on disease-specific mutations and underscore distinguishing morphologic features. In this context, it seems to be reasonable to compare first major diagnostic criteria of the former WHO classifications for myeloproliferative neoplasm (MPN) and then to focus on details that have been discussed and will be proposed for the upcoming revision of diagnostic guidelines. In PV, a characteristic bone marrow (BM) morphology was added as one of three major diagnostic criteria, which allowed lowering of the hemoglobin/hematocrit threshold for diagnosis, which is another major criterion, to 16.5 g/dl/49% in men and 16 g/dl/48% in women. The presence of a JAK2 mutation remains the third major diagnostic criterion in PV. Subnormal serum erythropoietin level is now the only minor criterion in PV and is used to capture JAK2-unmutated cases. In ET and PMF, mutations that are considered to confirm clonality and specific diagnosis now include CALR, in addition to JAK2 and MPL. Also in the 2015 discussed revision, overtly fibrotic PMF is clearly distinguished from early/prefibrotic PMF and each PMF variant now includes a separate list of diagnostic criteria. The main rationale for these changes was to enhance the distinction between so-called masked PV and JAK2-mutated ET and between ET and prefibrotic early PMF. The proposed changes also underscore the complementary role, as well as limitations of mutation analysis in morphologic diagnosis. On the other hand, discovery of new biological markers may probably be expected in the future to enhance discrimination of the different MPN subtypes in accordance with the histological BM patterns and corresponding clinical features. PMID:26832847

  17. Dysregulation of VEGF-induced proangiogenic Ca2+ oscillations in primary myelofibrosis-derived endothelial colony-forming cells.

    PubMed

    Dragoni, Silvia; Reforgiato, Marta; Zuccolo, Estella; Poletto, Valentina; Lodola, Francesco; Ruffinatti, Federico Alessandro; Bonetti, Elisa; Guerra, Germano; Barosi, Giovanni; Rosti, Vittorio; Moccia, Francesco

    2015-12-01

    Endothelial progenitor cells could be implicated in the aberrant neoangiogenesis that occurs in bone marrow and spleen in patients with primary myelofibrosis (PMF). However, antivascular endothelial growth factor (VEGF) monotherapy had only a modest and transient effect in these individuals. Recently it was found that VEGF-induced proangiogenic intracellular Ca(2+) oscillations could be impaired in endothelial progenitor cells of subjects with malignancies. Therefore, we employed Ca(2+) imaging, wavelet analysis, and functional assays to assess whether and how VEGF-induced Ca(2+) oscillations are altered in PMF-derived endothelial progenitor cells. We focused on endothelial colony-forming cells (ECFCs), which are the only endothelial progenitor cell subtype capable of forming neovessels both in vivo and in vitro. VEGF triggers repetitive Ca(2+) spikes in both normal ECFCs (N-ECFCs) and ECFCs obtained from PMF patients (PMF-ECFCs). However, the spiking response to VEGF is significantly weaker in PMF-ECFCs. VEGF-elicited Ca(2+) oscillations are patterned by the interaction between inositol-1,4,5-trisphosphate-dependent Ca(2+) mobilization and store-operated Ca(2+) entry. However, in most PMF-ECFCs, Ca(2+) oscillations are triggered by a store-independent Ca(2+) entry pathway. We found that diacylglycerol gates transient receptor potential canonical 1 channel to trigger VEGF-dependent Ca(2+) spikes by recruiting the phospholipase C/inositol-1,4,5-trisphosphate signaling pathway, reflected as a decrease in endoplasmic reticulum Ca(2+) content. Finally, we found that, apart from being less robust and dysregulated as compared with N-ECFCs, VEGF-induced Ca(2+) oscillations modestly stimulate PMF-ECFC growth and in vitro angiogenesis. These results may explain the modest effect of anti-VEGF therapies in PMF. PMID:26432919

  18. A Pilot Study of Quantitative MRI Parametric Response Mapping of Bone Marrow Fat for Treatment Assessment in Myelofibrosis

    PubMed Central

    Luker, Gary D.; Nguyen, Huong (Marie); Hoff, Benjamin A.; Galbán, Craig J.; Hernando, Diego; Chenevert, Thomas L.; Talpaz, Moshe; Ross, Brian D.

    2016-01-01

    Myelofibrosis (MF) is a hematologic neoplasm arising as a primary disease or secondary to other myeloproliferative neoplasms (MPNs). Both primary and secondary MF are uniquely associated with progressive bone marrow fibrosis, displacing normal hematopoietic cells from the marrow space and disrupting normal production of mature blood cells. Activation of the JAK2 signaling pathway in hematopoietic stem cells commonly causes MF, and ruxolitinib, a drug targeting this pathway, is the treatment of choice for many patients. However, current measures of disease status in MF do not necessarily predict response to treatment with ruxolitinib or other drugs in MF. Bone marrow biopsies are invasive and prone to sampling error, while measurements of spleen volume only indirectly reflect bone marrow status. Toward the goal of developing an imaging biomarker for treatment response in MF, we present preliminary results from a prospective clinical study evaluating parametric response mapping (PRM) of quantitative Dixon MRI bone marrow fat fraction maps in four MF patients treated with ruxolitinib. PRM allows for the voxel-wise identification of significant change in quantitative imaging readouts over time, in this case the bone marrow fat content. We identified heterogeneous response patterns of bone marrow fat among patients and within different bone marrow sites in the same patient. We also observed discordance between changes in bone marrow fat fraction and reductions in spleen volume, the standard imaging metric for treatment efficacy. This study provides initial support for PRM analysis of quantitative MRI of bone marrow fat to monitor response to therapy in MF, setting the stage for larger studies to further develop and validate this method as a complementary imaging biomarker for this disease. PMID:27213182

  19. Allogeneic stem cell transplant for myelofibrosis patients over age 60: likely impact of the JAK2 inhibitors

    PubMed Central

    Fauble, V; Leis, J; Mesa, R A

    2012-01-01

    The myeloproliferative neoplasm, myelofibrosis (MF), has only one therapeutic intervention that is potentially curative in these individuals, specifically that of allogeneic stem cell transplantation (ASCT). ASCT has been utilized up to this juncture, primarily in younger individuals with higher risk disease. There is more limited data on outcomes in individuals over the age of 60 years. The choice of an individualized therapeutic intervention for a patient with MF is a very complex issue and is dependent on several factors. The first factor being their overall prognosis with their illness (which can vary from a median of 2 years in high-risk patients to over 10 years in low-risk patients) and the potential impact of a therapeutic intervention not only on survival but also on quality of life. Current available therapies have been strictly palliative for disease-associated anemia and/or splenomegaly. At present, we have a new generation of inhibitors of JAK2 (Ruxolitinib, CYT387, SB1518, TG101348, with others in development), which have been shown to improve splenomegaly, improve symptomatic burden of illness and improve quality of life. In addition, these inhibitors of JAK2 may have an impact on the natural history of MF, but confirmation of the presence and degree of this impact is still pending. Clinical availability of JAK2 inhibitors may alter the timing of transplant in marginal transplant candidates (that is, those over the age of 60), may have a role preceding ASCT to improve spleen size and performance status before transplant and might be frontline therapy in intermediate and high-risk patients who are not candidates for ASCT. PMID:27175229

  20. Loss of Ezh2 synergizes with JAK2-V617F in initiating myeloproliferative neoplasms and promoting myelofibrosis.

    PubMed

    Shimizu, Takafumi; Kubovcakova, Lucia; Nienhold, Ronny; Zmajkovic, Jakub; Meyer, Sara C; Hao-Shen, Hui; Geier, Florian; Dirnhofer, Stephan; Guglielmelli, Paola; Vannucchi, Alessandro M; Feenstra, Jelena D Milosevic; Kralovics, Robert; Orkin, Stuart H; Skoda, Radek C

    2016-07-25

    Myeloproliferative neoplasm (MPN) patients frequently show co-occurrence of JAK2-V617F and mutations in epigenetic regulator genes, including EZH2 In this study, we show that JAK2-V617F and loss of Ezh2 in hematopoietic cells contribute synergistically to the development of MPN. The MPN phenotype induced by JAK2-V617F was accentuated in JAK2-V617F;Ezh2(-/-) mice, resulting in very high platelet and neutrophil counts, more advanced myelofibrosis, and reduced survival. These mice also displayed expansion of the stem cell and progenitor cell compartments and a shift of differentiation toward megakaryopoiesis at the expense of erythropoiesis. Single cell limiting dilution transplantation with bone marrow from JAK2-V617F;Ezh2(+/-) mice showed increased reconstitution and MPN disease initiation potential compared with JAK2-V617F alone. RNA sequencing in Ezh2-deficient hematopoietic stem cells (HSCs) and megakaryocytic erythroid progenitors identified highly up-regulated genes, including Lin28b and Hmga2, and chromatin immunoprecipitation (ChIP)-quantitative PCR (qPCR) analysis of their promoters revealed decreased H3K27me3 deposition. Forced expression of Hmga2 resulted in increased chimerism and platelet counts in recipients of retrovirally transduced HSCs. JAK2-V617F-expressing mice treated with an Ezh2 inhibitor showed higher platelet counts than vehicle controls. Our data support the proposed tumor suppressor function of EZH2 in patients with MPN and call for caution when considering using Ezh2 inhibitors in MPN. PMID:27401344

  1. Efficacy, safety, and survival with ruxolitinib in patients with myelofibrosis: results of a median 3-year follow-up of COMFORT-I.

    PubMed

    Verstovsek, Srdan; Mesa, Ruben A; Gotlib, Jason; Levy, Richard S; Gupta, Vikas; DiPersio, John F; Catalano, John V; Deininger, Michael W N; Miller, Carole B; Silver, Richard T; Talpaz, Moshe; Winton, Elliott F; Harvey, Jimmie H; Arcasoy, Murat O; Hexner, Elizabeth O; Lyons, Roger M; Raza, Azra; Vaddi, Kris; Sun, William; Peng, Wei; Sandor, Victor; Kantarjian, Hagop

    2015-04-01

    In the phase III COMFORT-I study, the Janus kinase 1 (JAK1)/JAK2 inhibitor ruxolitinib provided significant improvements in splenomegaly, key symptoms, and quality-of-life measures and was associated with an overall survival benefit relative to placebo in patients with intermediate-2 or high-risk myelofibrosis. This planned analysis assessed the long-term efficacy and safety of ruxolitinib at a median follow-up of 149 weeks. At data cutoff, approximately 50% of patients originally randomized to ruxolitinib remained on treatment whereas all patients originally assigned to placebo had discontinued or crossed over to ruxolitinib. At week 144, mean spleen volume reduction was 34% with ruxolitinib. Previously observed improvements in quality-of-life measures were sustained with longer-term ruxolitinib therapy. Overall survival continued to favor ruxolitinib despite the majority of placebo patients crossing over to ruxolitinib [hazard ratio 0.69 (95% confidence interval: 0.46-1.03); P = 0.067]. Exploratory analyses suggest that crossover may have contributed to an underestimation of the true survival difference between the treatment groups. Ruxolitinib continued to be generally well tolerated; there was no pattern of worsening grade ≥ 3 anemia or thrombocytopenia with longer-term ruxolitinib exposure. These longer-term data continue to support the efficacy and safety of ruxolitinib in patients with myelofibrosis. The study is registered at clinicaltrials.gov: NCT00952289. PMID:25616577

  2. Efficacy, safety, and survival with ruxolitinib in patients with myelofibrosis: results of a median 3-year follow-up of COMFORT-I

    PubMed Central

    Verstovsek, Srdan; Mesa, Ruben A.; Gotlib, Jason; Levy, Richard S.; Gupta, Vikas; DiPersio, John F.; Catalano, John V.; Deininger, Michael W.N.; Miller, Carole B.; Silver, Richard T.; Talpaz, Moshe; Winton, Elliott F.; Harvey, Jimmie H.; Arcasoy, Murat O.; Hexner, Elizabeth O.; Lyons, Roger M.; Raza, Azra; Vaddi, Kris; Sun, William; Peng, Wei; Sandor, Victor; Kantarjian, Hagop

    2015-01-01

    In the phase III COMFORT-I study, the Janus kinase 1 (JAK1)/JAK2 inhibitor ruxolitinib provided significant improvements in splenomegaly, key symptoms, and quality-of-life measures and was associated with an overall survival benefit relative to placebo in patients with intermediate-2 or high-risk myelofibrosis. This planned analysis assessed the long-term efficacy and safety of ruxolitinib at a median follow-up of 149 weeks. At data cutoff, approximately 50% of patients originally randomized to ruxolitinib remained on treatment whereas all patients originally assigned to placebo had discontinued or crossed over to ruxolitinib. At week 144, mean spleen volume reduction was 34% with ruxolitinib. Previously observed improvements in quality-of-life measures were sustained with longer-term ruxolitinib therapy. Overall survival continued to favor ruxolitinib despite the majority of placebo patients crossing over to ruxolitinib [hazard ratio 0.69 (95% confidence interval: 0.46–1.03); P=0.067]. Exploratory analyses suggest that crossover may have contributed to an underestimation of the true survival difference between the treatment groups. Ruxolitinib continued to be generally well tolerated; there was no pattern of worsening grade ≥3 anemia or thrombocytopenia with longer-term ruxolitinib exposure. These longer-term data continue to support the efficacy and safety of ruxolitinib in patients with myelofibrosis. The study is registered at clinicaltrials.gov: NCT00952289. PMID:25616577

  3. A phase 2 randomized dose-ranging study of the JAK2-selective inhibitor fedratinib (SAR302503) in patients with myelofibrosis

    PubMed Central

    Pardanani, A; Tefferi, A; Jamieson, C; Gabrail, N Y; Lebedinsky, C; Gao, G; Liu, F; Xu, C; Cao, H; Talpaz, M

    2015-01-01

    In this phase 2 open-label randomized study, 31 patients with intermediate-2 or high-risk myelofibrosis received fedratinib 300, 400 or 500 mg once daily in consecutive 4-week cycles. Mean spleen volume reductions at 12 weeks (primary end point) were 30.3% (300 mg), 33.1% (400 mg) and 43.3% (500 mg). Spleen response rates (patients achieving ⩾35% spleen reduction) at 12/24 weeks were 30%/30% (300 mg), 50%/60% (400 mg) and 64%/55% (500 mg), respectively. By 4 weeks, improvements in myelofibrosis (MF)-associated symptoms were observed. At 48 weeks, 68% of patients remained on fedratinib and 16% had discontinued because of adverse events (AEs). Common grade 3/4 AEs were anemia (58%), fatigue (13%), diarrhea (13%), vomiting (10%) and nausea (6%). Serious AEs included one case of reversible hepatic failure and one case of Wernicke's encephalopathy (after analysis cutoff). Fedratinib treatment led to reduced STAT3 phosphorylation but no meaningful change in JAK2V617F allele burden. Significant modulation (P<0.05, adjusted for multiple comparisons) of 28 cytokines was observed, many of which correlated with spleen reduction. These data confirm the clinical activity of fedratinib in MF. After the analysis cutoff date, additional reports of Wernicke's encephalopathy in other fedratinib trials led to discontinuation of the sponsored clinical development program. PMID:26252788

  4. Enhanced Expression of Stim, Orai, and TRPC Transcripts and Proteins in Endothelial Progenitor Cells Isolated from Patients with Primary Myelofibrosis

    PubMed Central

    Dragoni, Silvia; Laforenza, Umberto; Bonetti, Elisa; Reforgiato, Marta; Poletto, Valentina; Lodola, Francesco; Bottino, Cinzia; Guido, Daniele; Rappa, Alessandra; Pareek, Sumedha; Tomasello, Mario; Guarrera, Maria Rosa; Cinelli, Maria Pia; Aronica, Adele; Guerra, Germano; Barosi, Giovanni; Tanzi, Franco

    2014-01-01

    Background An increase in the frequency of circulating endothelial colony forming cells (ECFCs), the only subset of endothelial progenitor cells (EPCs) truly belonging to the endothelial phenotype, occurs in patients affected by primary myelofibrosis (PMF). Herein, they might contribute to the enhanced neovascularisation of fibrotic bone marrow and spleen. Store-operated Ca2+ entry (SOCE) activated by the depletion of the inositol-1,4,5-trisphosphate (InsP3)-sensitive Ca2+ store drives proliferation in ECFCs isolated from both healthy donors (N-ECFCs) and subjects suffering from renal cellular carcinoma (RCC-ECFCs). SOCE is up-regulated in RCC-ECFCs due to the over-expression of its underlying molecular components, namely Stim1, Orai1, and TRPC1. Methodology/Principal Findings We utilized Ca2+ imaging, real-time polymerase chain reaction, western blot analysis and functional assays to evaluate molecular structure and the functional role of SOCE in ECFCs derived from PMF patients (PMF-ECFCs). SOCE, induced by either pharmacological (i.e. cyclopiazonic acid or CPA) or physiological (i.e. ATP) stimulation, was significantly higher in PMF-ECFCs. ATP-induced SOCE was inhibited upon blockade of the phospholipase C/InsP3 signalling pathway with U73111 and 2-APB. The higher amplitude of SOCE was associated to the over-expression of the transcripts encoding for Stim2, Orai2–3, and TRPC1. Conversely, immunoblotting revealed that Stim2 levels remained constant as compared to N-ECFCs, while Stim1, Orai1, Orai3, TRPC1 and TRPC4 proteins were over-expressed in PMF-ECFCs. ATP-induced SOCE was inhibited by BTP-2 and low micromolar La3+ and Gd3+, while CPA-elicited SOCE was insensitive to Gd3+. Finally, BTP-2 and La3+ weakly blocked PMF-ECFC proliferation, while Gd3+ was ineffective. Conclusions Two distinct signalling pathways mediate SOCE in PMF-ECFCs; one is activated by passive store depletion and is Gd3+-resistant, while the other one is regulated by the InsP3-sensitive Ca2

  5. Epidemiology and clinical relevance of mutations in postpolycythemia vera and postessential thrombocythemia myelofibrosis: A study on 359 patients of the AGIMM group.

    PubMed

    Rotunno, Giada; Pacilli, Annalisa; Artusi, Valentina; Rumi, Elisa; Maffioli, Margherita; Delaini, Federica; Brogi, Giada; Fanelli, Tiziana; Pancrazzi, Alessandro; Pietra, Daniela; Bernardis, Isabella; Belotti, Clara; Pieri, Lisa; Sant'Antonio, Emanuela; Salmoiraghi, Silvia; Cilloni, Daniela; Rambaldi, Alessandro; Passamonti, Francesco; Barbui, Tiziano; Manfredini, Rossella; Cazzola, Mario; Tagliafico, Enrico; Vannucchi, Alessandro M; Guglielmelli, Paola

    2016-07-01

    Transformation to secondary myelofibrosis (MF) occurs as part of the natural history of polycythemia vera (PPV-MF) and essential thrombocythemia (PET-MF). Although primary (PMF) and secondary MF are considered similar diseases and managed similarly, there are few studies specifically focused on the latter. The aim of this study was to characterize the mutation landscape, and describe the main clinical correlates and prognostic implications of mutations, in a series of 359 patients with PPV-MF and PET-MF. Compared with PV and ET, the JAK2V617F and CALR mutated allele burden was significantly higher in PPV-MF and/or PET-MF, indicating a role for accumulation of mutated alleles in the process of transformation to MF. However, neither the allele burden nor the type of driver mutation influenced overall survival (OS), while absence of any driver mutation (triple negativity) was associated with significant reduction of OS in PET-MF, similar to PMF. Of the five interrogated subclonal mutations (ASXL1, EZH2, SRSF2, IDH1, and IDH2), that comprise a prognostically detrimental high molecular risk (HMR) category in PMF, only SRSF2 mutations were associated with reduced survival in PET-MF, and no additional mutation profile with prognostic relevance was highlighted. Overall, these data indicate that the molecular landscape of secondary forms of MF is different from PMF, suggesting that unknown mutational events might contribute to the progression from chronic phase disease to myelofibrosis. These findings also support more extended genotyping approaches aimed at identifying novel molecular abnormalities with prognostic relevance for patients with PPV-MF and PET-MF. Am. J. Hematol. 91:681-686, 2016. © 2016 Wiley Periodicals, Inc. PMID:27037840

  6. Post clamp

    NASA Technical Reports Server (NTRS)

    Ramsey, John K. (Inventor); Meyn, Erwin H. (Inventor)

    1990-01-01

    A pair of spaced collars are mounted at right angles on a clamp body by retaining rings which enable the collars to rotate with respect to the clamp body. Mounting posts extend through aligned holes in the collars and clamp body. Each collar can be clamped onto the inserted post while the clamp body remains free to rotate about the post and collar. The clamp body is selectively clamped onto each post.

  7. Myelofibrosis 2012: it's complicated.

    PubMed

    Hubbeling, Harper G; Frank, Dale M; Hexner, Elizabeth O

    2012-06-01

    Major advances in myeloproliferative neoplasms in the last decade have cast light on their complexity. The identification of JAK2 (V617F) briefly promised a unifying mechanism of pathogenesis with a single pathway that could be efficiently targeted. Instead, there have been major advances in understanding acquired and background genetic and epigenetic contributors to this group of disorders, with refined risk prediction models and experimental therapeutics that have provided a more nuanced model of disease. In aggregate these observations likely explain the heterogeneity of these disorders and their generally unpredictable response to therapy. Molecular studies, beginning with the identification of JAK2 (V617F), have led to a concept of MPN subtypes existing on a continuum, and additional discoveries such as TET2 and EZH2 mutations have provided the molecular underpinnings to begin to explain overlapping phenotypes in myeloid malignancies more generally. In many ways the pace of molecular discovery is outstripping our ability to integrate these observations into clinical care, both in terms of molecular diagnostics and medical decision making. This review will attempt to summarize, within a clinical context, our evolving understanding of myeloproliferative neoplasms. It focuses on biology, histopathology, prognostic scoring systems, stem cell transplantation as well as selected clinical/preclinical therapeutic observations. PMID:23556120

  8. A phase I, open-label, multi-center study of the JAK2 inhibitor AZD1480 in patients with myelofibrosis.

    PubMed

    Verstovsek, Srdan; Hoffman, Ronald; Mascarenhas, John; Soria, Jean-Charles; Bahleda, Ratislav; McCoon, Patricia; Tang, Weifeng; Cortes, Jorge; Kantarjian, Hagop; Ribrag, Vincent

    2015-02-01

    The anti-tumor activity of AZD1480, a potent, selective inhibitor of Janus-associated kinases 1 and 2, was demonstrated in preclinical models of myeloproliferative neoplasms. In a phase I clinical study, 35 patients with myelofibrosis received 2.5-70mg AZD1480 orally once daily (QD) or 10 or 15mg twice daily (BID) continuously during repeated 28-day cycles. Two patients experienced dose-limiting toxicities: one patient in the 2.5mg QD cohort had a grade 3 lung infiltration/acute pneumonia, and one patient receiving 50mg QD had grade 3 presyncope. Dosing was stopped at 70mg QD after the first patient experienced an adverse neurological event (AE) and evidence of low-grade neurological toxicity in patients on lower doses after the initial month of therapy became apparent. The most common AZD1480-related AEs were dizziness and anemia. AZD1480 was absorbed quickly and eliminated from the plasma rapidly, with a mean terminal half-life of 2.45-8.06h; accumulation was not observed after repeated daily dosing for 28 days. Four patients showed evidence of clinical improvement based on IWG-MRT 2006 criteria. AZD1480 was relatively well tolerated, however, low-grade, reversible neurological toxicity was therapy limiting and led to study termination. PMID:25530567

  9. Revised response criteria for myelofibrosis: International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) consensus report

    PubMed Central

    Cervantes, Francisco; Mesa, Ruben; Passamonti, Francesco; Verstovsek, Srdan; Vannucchi, Alessandro M.; Gotlib, Jason; Dupriez, Brigitte; Pardanani, Animesh; Harrison, Claire; Hoffman, Ronald; Gisslinger, Heinz; Kröger, Nicolaus; Thiele, Juergen; Barbui, Tiziano; Barosi, Giovanni

    2013-01-01

    The current document is a revision of the International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) criteria for treatment response in myelofibrosis (MF) and represents a collaborative effort by the IWG-MRT and the European LeukemiaNet to objectively assess the value of new drugs in inducing morphologic remission or improvement in MF-associated symptomatic burden (MF-SB). Some of the changes in the current revision include stricter definitions of red cell transfusion dependency and independency and consideration of the Myeloproliferative Neoplasm Symptom Assessment Form as a tool to quantify meaningful changes in disease-related symptoms. Six response categories are listed: complete remission (CR) and partial remission signify treatment effects that are consistent with disease modification, whereas drug-induced improvements in MF-SB were annotated as clinical improvement, anemia response, spleen response, or symptoms response. Additional criteria are provided for progressive disease, stable disease, and relapse. The document also includes recommendations for assessing cytogenetic and molecular remissions, without mandating their inclusion for CR assignment. PMID:23838352

  10. Therapeutic benefit of decitabine, a hypomethylating agent, in patients with high-risk primary myelofibrosis and myeloproliferative neoplasm in accelerated or blastic/acute myeloid leukemia phase.

    PubMed

    Badar, Talha; Kantarjian, Hagop M; Ravandi, Farhad; Jabbour, Elias; Borthakur, Gautam; Cortes, Jorge E; Pemmaraju, Naveen; Pierce, Sherry R; Newberry, Kate J; Daver, Naval; Verstovsek, Srdan

    2015-09-01

    Myeloproliferative neoplasm (MPN) transformed to acute myeloid leukemia (MPN-AML), MPN in accelerated phase (MPN-AP), and high-risk primary myelofibrosis (PMF) are associated with a poor response to therapy and very short survival. Several reports have suggested clinical activity of hypomethylating agents in these patients. We conducted a retrospective study of 21 patients with MPN-AML, 13 with MPN-AP and 11 with DIPSS-plus high-risk PMF treated with decitabine at our institution over the last 7 years and evaluated their clinical outcomes. Six patients (29%) with MPN-AML responded to decitabine (3 CR, 2 CRi, and 1 PR); median response duration was 7 months. The median overall survival (OS) was significantly higher in those who responded (10.5 vs 4 months). Among patients with MPN-AP, 8 patients (62%) benefited; the median response duration was 6.5 months. The median OS was 11.8 months in responders vs 4.7 months in non-responders. Among patients with DIPSS-plus high-risk PMF, 9 (82%) benefited; the median response duration was 9 months. The median OS was 32 months in responders vs 16.3 months in non-responders. Decitabine is a viable therapeutic option for patients with MPN-AML, MP-AP and high-risk PMF. Prospective clinical studies combining decitabine with other clinically active agents are needed to improve overall outcome. PMID:26183878

  11. miRNA-mRNA integrative analysis in primary myelofibrosis CD34+ cells: role of miR-155/JARID2 axis in abnormal megakaryopoiesis.

    PubMed

    Norfo, Ruggiero; Zini, Roberta; Pennucci, Valentina; Bianchi, Elisa; Salati, Simona; Guglielmelli, Paola; Bogani, Costanza; Fanelli, Tiziana; Mannarelli, Carmela; Rosti, Vittorio; Pietra, Daniela; Salmoiraghi, Silvia; Bisognin, Andrea; Ruberti, Samantha; Rontauroli, Sebastiano; Sacchi, Giorgia; Prudente, Zelia; Barosi, Giovanni; Cazzola, Mario; Rambaldi, Alessandro; Bortoluzzi, Stefania; Ferrari, Sergio; Tagliafico, Enrico; Vannucchi, Alessandro M; Manfredini, Rossella

    2014-09-25

    Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by megakaryocyte (MK) hyperplasia, bone marrow fibrosis, and abnormal stem cell trafficking. PMF may be associated with somatic mutations in JAK2, MPL, or CALR. Previous studies have shown that abnormal MKs play a central role in the pathophysiology of PMF. In this work, we studied both gene and microRNA (miRNA) expression profiles in CD34(+) cells from PMF patients. We identified several biomarkers and putative molecular targets such as FGR, LCN2, and OLFM4. By means of miRNA-gene expression integrative analysis, we found different regulatory networks involved in the dysregulation of transcriptional control and chromatin remodeling. In particular, we identified a network gathering several miRNAs with oncogenic potential (eg, miR-155-5p) and targeted genes whose abnormal function has been previously associated with myeloid neoplasms, including JARID2, NR4A3, CDC42, and HMGB3. Because the validation of miRNA-target interactions unveiled JARID2/miR-155-5p as the strongest relationship in the network, we studied the function of this axis in normal and PMF CD34(+) cells. We showed that JARID2 downregulation mediated by miR-155-5p overexpression leads to increased in vitro formation of CD41(+) MK precursors. These findings suggest that overexpression of miR-155-5p and the resulting downregulation of JARID2 may contribute to MK hyperplasia in PMF. PMID:25097177

  12. REDUCED INTENSITY HEMATOPOIETIC CELL TRANSPLANTATION FOR PATIENTS WITH PRIMARY MYELOFIBROSIS: A COHORT ANALYSIS FROM THE CENTER FOR INTERNATIONAL BLOOD AND MARROW TRANSPLANT RESEARCH

    PubMed Central

    Gupta, Vikas; Malone, Adriana K.; Hari, Parameswaran N.; Ahn, Kwang Woo; Hu, Zhen-Huan; Gale, Robert Peter; Ballen, Karen K.; Hamadani, Mehdi; Olavarria, Eduardo; Gerds, Aaron T.; Waller, Edmund K.; Costa, Luciano J.; Antin, Joseph H.; Kamble, Rammurti T.; van Besien, Koen M.; Savani, Bipin N.; Schouten, Harry C.; Szer, Jeffrey; Cahn, Jean-Yves; de Lima, Marcos J.; Wirk, Baldeep; Aljurf, Mahmoud D.; Popat, Uday; Bejanyan, Nelli; Litzow, Mark R.; Norkin, Maxim; Lewis, Ian D.; Hale, Gregory A.; Woolfrey, Ann E.; Miller, Alan M.; Ustun, Celalettin; Jagasia, Madan H.; Lill, Michael; Maziarz, Richard T.; Cortes, Jorge; Kalaycio, Matt E.; Saber, Wael

    2014-01-01

    We evaluated the outcomes and associated prognostic factors in 233 patients undergoing allogeneic hematopoietic cell transplantation (HCT) for primary myelofibrosis (MF) using reduced intensity conditioning (RIC). Median age at HCT was 55 years. Donors were: matched sibling donor (MSD), 34%; HLA-well-matched unrelated donors (URD), 45%; and partially/mismatched URD, 21%. Risk stratification according to Dynamic International Prognostic Scoring System (DIPSS): low, 12%; intermediate-1, 49%; intermediate-2, 37%; and high, 1%. The probability of survival at 5-years was 47% (95% CI 40–53). In a multivariate analysis, donor type was the only independent factor associated with survival. Adjusted probabilities of survival at 5-years for MSD, well matched URD and partially matched/mismatched URD were 56% (95% CI 44–67), 48% (95% CI 37–58), and 34% (95% CI 21–47), respectively (p=0.002). Relative risks (RR) for NRM for well-matched URD and partially matched/mismatched URD were 3.92 (p=0.006) and 9.37 (p<0.0001), respectively. A trend towards increased NRM (RR 1.7, p=0.07) and inferior survival (RR 1.37, p=0.10) was observed in DIPSS-intermediate-2/high-risk patients compared to DIPSS-low/intermediate-1 risk patients. RIC HCT is a potentially curative option for patients with MF, and donor type is the most important factor influencing survival in these patients. PMID:24161923

  13. JAK2 Exon 14 Skipping in Patients with Primary Myelofibrosis: A Minor Splice Variant Modulated by the JAK2-V617F Allele Burden

    PubMed Central

    Catarsi, Paolo; Rosti, Vittorio; Morreale, Giacomo; Poletto, Valentina; Villani, Laura; Bertorelli, Roberto; Pedrazzini, Matteo; Zorzetto, Michele; Barosi, Giovanni

    2015-01-01

    Background Primary myelofibrosis (PMF) is an acquired clonal disease of the hematopoietic stem cell compartment, characterized by bone marrow fibrosis, anemia, splenomegaly and extramedullary hematopoiesis. About 60% of patients with PMF harbor a somatic mutation of the JAK2 gene (JAK2-V617F) in their hematopoietic lineage. Recently, a splicing isoform of JAK2, lacking exon 14 (JAK2Δ14) was described in patients affected by myeloproliferative diseases. Materials and Methods By using a specific RT-qPCR method, we measured the ratio between the splicing isoform and the JAK2 full-length transcript (JAK2+14) in granulocytes, isolated from peripheral blood, of forty-four patients with PMF and nine healthy donors. Results We found that JAK2Δ14 was only slightly increased in patients and, at variance with published data, the splicing isoform was also detectable in healthy controls. We also found that, in patients bearing the JAK2-V617F mutation, the percentage of mutated alleles correlated with the observed increase in JAK2Δ14. Homozygosity for the mutation was also associated with a higher level of JAK2+14. Bioinformatic analysis indicates the possibility that the G>T transversion may interfere with the correct splicing of exon 14 by modifying a splicing regulatory sequence. Conclusions Increased levels of JAK2 full-length transcript and a small but significant increase in JAK2 exon 14 skipping, are associated with the JAK2-V617F allele burden in PMF granulocytes. Our data do not confirm a previous claim that the production of the JAK2Δ14 isoform is related to the pathogenesis of PMF. PMID:25617626

  14. IDH mutations in primary myelofibrosis predict leukemic transformation and shortened survival: clinical evidence for leukemogenic collaboration with JAK2V617F.

    PubMed

    Tefferi, A; Jimma, T; Sulai, N H; Lasho, T L; Finke, C M; Knudson, R A; McClure, R F; Pardanani, A

    2012-03-01

    Isocitrate dehydrogenase (IDH) mutations are frequent in blast-phase myeloproliferative neoplasms and might therefore contribute to leukemic transformation. We examined this possibility in 301 consecutive patients with chronic-phase primary myelofibrosis (PMF). The mutant IDH was detected in 12 patients (4%): 7 IDH2 (5 R140Q, 1 R140W and 1 R172G) and 5 IDH1 (3 R132S and 2 R132C). In all, 6 (50%) of the 12 IDH-mutated patients also expressed JAK2V617F. Overall, 18 (6%) patients displayed only MPL and 164 (54.3%) only JAK2 mutations. Multivariable analysis that accounted for conventional risk factors disclosed inferior overall survival (OS; P=0.03) and leukemia-free survival (LFS; P=0.003) in IDH-mutated patients: OS hazard ratio (HR) was 0.39 (95% confidence interval (95% CI) 0.2-0.75), 0.50 (95% CI 0.27-0.95) and 0.53 (95% CI 0.23-1.2) for patients with no, JAK2 or MPL mutations, respectively. Further analysis disclosed a more pronounced effect for the mutant IDH on OS and LFS in the presence (P=0.0002 and P<0.0001, respectively) as opposed to the absence (P=0.34 and P=0.64) of concomitant JAK2V617F. Analysis of paired samples obtained during chronic- and blast-phase disease revealed the presence of both IDH and JAK2 mutations at both time points. Our observations suggest that IDH mutations in PMF are independent predictors of leukemic transformation and raise the possibility of leukemogenic collaboration with JAK2V617F. PMID:21912393

  15. A pooled analysis of overall survival in COMFORT-I and COMFORT-II, 2 randomized phase III trials of ruxolitinib for the treatment of myelofibrosis

    PubMed Central

    Vannucchi, Alessandro M.; Kantarjian, Hagop M.; Kiladjian, Jean-Jacques; Gotlib, Jason; Cervantes, Francisco; Mesa, Ruben A.; Sarlis, Nicholas J.; Peng, Wei; Sandor, Victor; Gopalakrishna, Prashanth; Hmissi, Abdel; Stalbovskaya, Viktoriya; Gupta, Vikas; Harrison, Claire; Verstovsek, Srdan

    2015-01-01

    Ruxolitinib, a potent Janus kinase 1/2 inhibitor, resulted in rapid and durable improvements in splenomegaly and disease-related symptoms in the 2 phase III COMFORT studies. In addition, ruxolitinib was associated with prolonged survival compared with placebo (COMFORT-I) and best available therapy (COMFORT-II). We present a pooled analysis of overall survival in the COMFORT studies using an intent-to-treat analysis and an analysis correcting for crossover in the control arms. Overall, 301 patients received ruxolitinib (COMFORT-I, n=155; COMFORT-II, n=146) and 227 patients received placebo (n=154) or best available therapy (n=73). After a median three years of follow up, intent-to-treat analysis showed that patients who received ruxolitinib had prolonged survival compared with patients who received placebo or best available therapy [hazard ratio=0.65; 95% confidence interval (95%CI): 0.46–0.90; P=0.01]; the crossover-corrected hazard ratio was 0.29 (95%CI: 0.13–0.63). Both patients with intermediate-2– or high-risk disease showed prolonged survival, and patients with high-risk disease in the ruxolitinib group had survival similar to that of patients with intermediate-2–risk disease in the control group. The Kaplan-Meier estimate of overall survival at week 144 was 78% in the ruxolitinib arm, 61% in the intent-to-treat control arm, and 31% in the crossover-adjusted control arm. While larger spleen size at baseline was prognostic for shortened survival, reductions in spleen size with ruxolitinib treatment correlated with longer survival. These findings are consistent with previous reports and support that ruxolitinib offers a survival benefit for patients with myelofibrosis compared with conventional therapies. (clinicaltrials.gov identifiers: COMFORT-I, NCT00952289; COMFORT-II, NCT00934544) PMID:26069290

  16. Dynamic Model for Predicting Death Within 12 Months in Patients With Primary or Post–Polycythemia Vera/Essential Thrombocythemia Myelofibrosis

    PubMed Central

    Tam, Constantine S.; Kantarjian, Hagop; Cortes, Jorge; Lynn, Alice; Pierce, Sherry; Zhou, Lingsha; Keating, Michael J.; Thomas, Deborah A.; Verstovsek, Srdan

    2009-01-01

    Purpose Current prognostic tools in myelofibrosis (MF) fail to identify patients at the highest risk of death and are limited by their applicability only to the time of diagnosis. We aimed to define an accelerated phase (AP) in MF by characterizing disease features that can identify patients with median overall survival of ≤ 12 months at any time in the disease course. Patients and Methods Baseline characteristics of 370 consecutive patients with MF from a single center were analyzed to identify features associated with a median overall survival of ≤ 12 months. These putative AP features were then validated by following the course of chronic-phase patients (no AP features at baseline) until the development of one or more AP features and determining their subsequent survival. Results The following three characteristics were associated with poor survival at baseline and were selected as putative AP features: blasts in blood or bone marrow ≥ 10%, platelets less than 50 × 109/L, and chromosome 17 aberrations (median overall survival, 10, 12, and 5 months, respectively). In the validation phase, chronic-phase patients who developed AP features during follow-up were found to have short subsequent survival times (median overall survival, 12, 15, and 6 months, respectively). AP was a necessary step in the progression to blast phase, with leukemic transformation being exceedingly rare (3% risk at 10 years) in patients who remained persistently in chronic phase. Conclusion Blood or bone marrow blasts ≥ 10%, platelets less than 50 × 109/L, and chromosome 17 aberrations defined AP in patients with MF. Patients in AP should be candidates for intensive therapeutic interventions. PMID:19786661

  17. Biological post

    PubMed Central

    Kumar, B. Suresh; Kumar, Senthil; Mohan Kumar, N. S.; Karunakaran, J. V.

    2015-01-01

    Anterior tooth fracture as a result of traumatic injuries, is frequently encountered in endodontic practice. Proper reconstruction of extensively damaged teeth can be achieved through the fragment reattachment procedure known as “biological restoration.” This case report refers to the esthetics and functional recovery of extensively damaged maxillary central incisor through the preparation and adhesive cementation of “biological post” in a young patient. Biological post obtained through extracted teeth from another individual–represent a low-cost option and alternative technique for the morphofunctional recovery of extensively damaged anterior teeth. PMID:26538952

  18. Loss of Ezh2 cooperates with Jak2V617F in the development of myelofibrosis in a mouse model of myeloproliferative neoplasm.

    PubMed

    Yang, Yue; Akada, Hajime; Nath, Dipmoy; Hutchison, Robert E; Mohi, Golam

    2016-06-30

    An activating JAK2V617F mutation has been found in ∼50% patients with myelofibrosis (MF). Inactivating mutations in histone methyltransferase enhancer of zeste homolog 2 (EZH2) also have been observed in patients with MF. Interestingly, inactivating EZH2 mutations are often associated with JAK2V617F mutation in MF, although their contributions in the pathogenesis of MF remain elusive. To determine the effects of concomitant loss of EZH2 and JAK2V617F mutation in hematopoiesis, we generated Ezh2-deficient Jak2V617F-expressing mice. Whereas expression of Jak2V617F alone induced a polycythemia vera-like disease, concomitant loss of Ezh2 significantly reduced the red blood cell and hematocrit parameters but increased the platelet counts in Jak2V617F knock-in mice. Flow cytometric analysis showed impairment of erythroid differentiation and expansion of megakaryocytic precursors in Ezh2-deficient Jak2V617F mice. Moreover, loss of Ezh2 enhanced the repopulation capacity of Jak2V617F-expressing hematopoietic stem cells. Histopathologic analysis revealed extensive fibrosis in the bone marrow (BM) and spleen of Ezh2-deleted Jak2V617F mice. Transplantation of BM from Ezh2-deleted Jak2V617F mice into wild-type animals resulted in even faster progression to MF. Gene expression profiling and chromatin immunoprecipitation sequence analysis revealed that S100a8, S100a9, Ifi27l2a, and Hmga2 were transcriptionally derepressed, and the H3K27me3 levels in these gene promoters were significantly reduced on Ezh2 deletion in hematopoietic progenitors of Jak2V617F mice. Furthermore, overexpression of S100a8, S100a9, Ifi27l2a, or Hmga2 significantly increased megakaryocytic colonies in the BM of Jak2V617F mice, indicating a role for these Ezh2 target genes in altered megakaryopoiesis involved in MF. Overall, our results suggest that loss of Ezh2 cooperates with Jak2V617F in the development of MF in Jak2V617F-expressing mice. PMID:27081096

  19. Genetics Home Reference: primary myelofibrosis

    MedlinePlus

    ... from gene mutations that occur in early blood-forming cells after conception. These alterations are called somatic ... Free article on PubMed Central Klampfl T, Gisslinger H, Harutyunyan AS, Nivarthi H, Rumi E, Milosevic JD, ...

  20. Post-Adolescent Issues

    MedlinePlus

    Search COPING & HEALING CARING FOR A CHILD: POST-ADOLESCENT ISSUES As your child reaches adulthood, there will ... intake. New issues that you and your post adolescent child may want to discus together with his/ ...

  1. Strain balanced quantum posts

    SciTech Connect

    Alonso-Alvarez, D.; Alen, B.; Ripalda, J. M.; Llorens, J. M.; Taboada, A. G.; Briones, F.; Roldan, M. A.; Hernandez-Saz, J.; Hernandez-Maldonado, D.; Herrera, M.; Molina, S. I.

    2011-04-25

    Quantum posts are assembled by epitaxial growth of closely spaced quantum dot layers, modulating the composition of a semiconductor alloy, typically InGaAs. In contrast with most self-assembled nanostructures, the height of quantum posts can be controlled with nanometer precision, up to a maximum value limited by the accumulated stress due to the lattice mismatch. Here, we present a strain compensation technique based on the controlled incorporation of phosphorous, which substantially increases the maximum attainable quantum post height. The luminescence from the resulting nanostructures presents giant linear polarization anisotropy.

  2. 19. GROUND STORY, POST OFFICE LOBBY DETAIL OF POST OFFICE ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    19. GROUND STORY, POST OFFICE LOBBY DETAIL OF POST OFFICE BOXES ALONG WEST WALL OF LEXINGTON AVENUE ARM - Grand Central Post Office Annex, Forty-fifth Street & Lexington Avenue, Southwest corner, New York County, NY

  3. 16. FLOOR 1; MASSIVE CENTER POST IS THE MAIN POST ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    16. FLOOR 1; MASSIVE CENTER POST IS THE MAIN POST OF A 1736 POST MILL WHICH THIS MILL REPLACED; MORTISE FOR QUARTER BAR CAN BE SEEN - Hook Windmill, North Main Street at Pantigo Road, East Hampton, Suffolk County, NY

  4. Cardiac function, microvascular structure, and capillary hematocrit in hearts of polycythemic rats.

    PubMed

    Rakusan, K; Cicutti, N; Kolar, F

    2001-12-01

    The effect of polycythemia on the coronary microcirculation was studied in young male rats. Two experimental models of polycythemia were employed: cobalt-induced polycythemia, which mimics hypoxia-induced changes, and erythropoietin-induced polycythemia, which circumvents these changes. In both models, baseline left ventricular function was normal, whereas maximal systolic and developed pressures were decreased. In cobalt-treated rats the left ventricular functional reserve was also compromised. Morphometric analysis of the left ventricle confirmed previously described improved geometric conditions for oxygen supply at the distal portions of capillaries (smaller domain areas and shorter capillary segments). In cobalt-treated but not in erythropoietin-treated rats, increased capillary angiogenesis was also detected. In the hearts from rats with both types of polycythemia, a small but significant increase in the formation of arterioles was found. Capillary linear hematocrit was within the normal range in both types of polycythemia despite sizeable increases in systemic hematocrit. Significant differences in red blood cell distribution within capillaries were found between proximal and distal portions in all experimental groups. PMID:11709408

  5. Time Course and Variability of Polycythemic Response in Men at High Altitude

    NASA Technical Reports Server (NTRS)

    Grover, R. F.; Seiland, M.; McCullough, R. G.; Greenleaf, J. E.; Dahms, T. E.; Wolfel, E.; Reeves, J. T.

    2000-01-01

    Ten young men were exposed to 4,300 m (PB 460 Torr) for three weeks. Plasma volume (PV, Evans Blue dye). and blood volume (BV, carbon monoxide) measured simultaneously, and red cell volume (RCV) calculated from hematocrit, were determined twice at sea level and after 9-11 and 19-20 days at high altitude. After 19-20 days. half the subjects increased RCV +19.4 +/- 1.8% (p<0.001); the other 5 subjects had no significant change in RCV. All 10 subjects had a sustained decrease in PV (-16.2 +/- 1.9%, p<0.05) at altitude. Consequently, compared with sea level values, BV was unchanged (-3.1 +/- 1.8%) in the group with increased RCV, but BV decreased significantly (-12.2 +/- 1.4%, p<0.05) in the other group. Variability in RCV response was not explained by differences, in hypoxemic stimulus or the erythropoictin and reticulocyte responses. Since RCV reflects the balance between red cell. production and destruction, accelerated red cell destruction may have occurred in those individuals with no net change in RCV.

  6. Post and Lintel Architecture

    ERIC Educational Resources Information Center

    Daniel, Robert A.

    1973-01-01

    Author finds that children understand architectural concepts more readily when he refers to familiar non-architectural examples of them such as goal posts, chairs, tables, and playground equipment. (GB)

  7. CRITICALITY SAFETY POSTING GUIDELINES

    SciTech Connect

    JENSEN, M.A.

    2001-11-01

    This document provides a set of guidelines in the preparation of criticality safety postings. Guidance is provided in word choice, word arrangement, common human factors considerations. and use of color to highlight limits, cautions, and permissives.

  8. Post-Polio Syndrome

    MedlinePlus

    ... Funding Information Research Programs Training & Career Awards Enhancing Diversity Find People About NINDS NINDS Post-Polio Syndrome ... News From NINDS | Find People | Training | Research | Enhancing Diversity Careers@NINDS | FOIA | Accessibility Policy | Contact Us | Privacy ...

  9. Cryogenic skirt support post

    NASA Astrophysics Data System (ADS)

    Niemann, R. C.; Buckles, W. E.

    The cold masses of cryostats having vertical axes, like vertical pressure vessels, can be effectively supported by means of a cylindrical skirt that wraps concentrically around the cold mass. The skirt is a cryogenic support post connected at its upper end to the cold mass and at its lower end to the cryostat vacuum vessel. A heat intercept connection to an intermediate temperature refrigeration source can be employed to control heat leak. The support post consists of a composite; e.g. epoxy fibreglass, or cylinder with bolted or thermal interference fit end connections. The support post, being a single element support, simplifies cryostat assembly and alignment. The composite cylinder, with a relatively large diameter, lends itself to structural soundness and stability under both static and dynamic loading conditions. Its relatively long length and intermediate temperature heat intercept allows low heat leak to the cold mass. The details of the design of a cryogenic skirt support post as applied to a superconducting magnetic energy storage cryostat are presented. Included are support post fabrication, cryostat assembly, and predicted structural and thermal performance. Fabrication of and operational experiences with a prototype support post assembly are discussed.

  10. Post-ERCP pancreatitis.

    PubMed

    Arata, Shinju; Takada, Tadahiro; Hirata, Koichi; Yoshida, Masahiro; Mayumi, Toshihiko; Hirota, Morihisa; Yokoe, Masamichi; Hirota, Masahiko; Kiriyama, Seiki; Sekimoto, Miho; Amano, Hodaka; Wada, Keita; Kimura, Yasutoshi; Gabata, Toshifumi; Takeda, Kazunori; Kataoka, Keisho; Ito, Tetsuhide; Tanaka, Masao

    2010-01-01

    Pancreatitis remains the most common severe complication of endoscopic retrograde cholangiopancreatography (ERCP). Detailed information about the findings of previous studies concerning post-ERCP pancreatitis has not been utilized sufficiently. The purpose of the present article was to present guidelines for the diagnostic criteria of post-ERCP pancreatitis, and its incidence, risk factors, and prophylactic procedures that are supported by evidence. To achieve this purpose, a critical examination was made of the articles on post-ERCP pancreatitis, based on the data obtained by research studies published up to 2009. At present, there are no standardized diagnostic criteria for post-ERCP pancreatitis. It is appropriate that post-ERCP pancreatitis is defined as acute pancreatitis that has developed following ERCP, and its diagnosis and severity assessment should be made according to the diagnostic criteria and severity assessment of the Japanese Ministry of Health, Labour and Welfare. The incidence of acute pancreatitis associated with diagnostic and therapeutic ERCP is 0.4-1.5 and 1.6-5.4%, respectively. Endoscopic papillary balloon dilation is associated with a high risk of acute pancreatitis compared with endoscopic sphincterotomy. It was made clear that important risk factors include dysfunction of the Oddi sphincter, being of the female sex, past history of post-ERCP pancreatitis, and performance of pancreaticography. Temporary prophylactic placement of pancreatic stents in the high-risk group is useful for the prevention of post-ERCP pancreatitis [odds ratio (OR) 3.2, 95% confidence interval (CI) 1.6-6.4, number needed to treat (NNT) 10]. Use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a reduction in the development of post-ERCP pancreatitis (OR 0.46, 95% CI 0.32-0.65). Single rectal administration of NSAIDs is useful for the prevention of post-ERCP pancreatitis [relative risk (RR) 0.36, 95% CI 0.22-0.60, NNT 15] and decreases the

  11. [Post bariatric body contouring.

    PubMed

    Winge, Rikke; Henriksen, Trine Foged; Printzlau, Andreas; Hülmich, Lisbet

    2014-03-17

    Post bariatric body contouring in Denmark is currently a field under development. The scope of this article is to give an overview of existing plastic surgery techniques being used to treat patients with massive weight loss, as well as the current indications for patient referral. Furthermore, we describe how to optimise the preoperative evaluation of the patient and give a brief description of potential surgical adverse effects and their prevalence. Further research can provide this field with invaluable data regarding the post-operative effects on patient rehabilitation and quality of life. PMID:25096208

  12. 1. Post card view of the bridge, c. 1910. Post ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    1. Post card view of the bridge, c. 1910. Post card courtesy Carol Poh Miller. Photocopy by Berni Rich, Score Photographers Cleveland, OH - B & O Railroad Bridge Number 464, Spanning Old Ship Canal & Cuyahoga River, Cleveland, Cuyahoga County, OH

  13. 10. FLOOR 1; CENTER POST AND POSTS UNDER STONE BEAMS ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    10. FLOOR 1; CENTER POST AND POSTS UNDER STONE BEAMS WHICH SUPPORT BRIDGE BEAMS FOR BRIDGE TREES; WEDGES FOR ADJUSTING HEIGHT OF BRIDGE TREE CAN BE SEEN - Shelter Island Windmill, Manwaring Road, Shelter Island, Suffolk County, NY

  14. 78 FR 2950 - Proposed Posting and Posting of Stockyards

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-01-15

    ... posted the stockyards. On January 26, 2010, we published a notice in the Federal Register (75 FR 4039... posting AZ-117 Robertson Horse Sales, Benson, April 28, 2010. Arizona. CA-193 Westside Auction...

  15. Typical Newel Post, First Floor Newel Post, Typical Baluster, Typical ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    Typical Newel Post, First Floor Newel Post, Typical Baluster, Typical Nosing, First Floor Stringer Profile, Second Floor Stringer Profile - National Home for Disabled Volunteer Soldiers - Battle Mountain Sanitarium, Treasurer's Quarters, 500 North Fifth Street, Hot Springs, Fall River County, SD

  16. Hemiparesis post cerebral malaria

    PubMed Central

    Taiaa, Oumkaltoum; Amil, Touriya; Darbi, Abdelatif

    2015-01-01

    Cerebral malaria is one of the most serious complications in the Plasmodium falciparum infection. In endemic areas, the cerebral malaria interested mainly children. The occurrence in adults is very rare and most interested adult traveling in tropical zones. This case report describes a motor deficit post cerebral malaria in a young adult traveling in malaria endemic area. This complication has been reported especially in children and seems very rare in adults. PMID:25995798

  17. Post-transplant hyperlipidaemia.

    PubMed Central

    Jindal, R. M.

    1997-01-01

    The correction of post-transplant hyperlipidaemia warrants the judicious and timely use of pharmacological agents with dietary modification and exercise. Reduction in hyperlipidaemia may have some role in decreasing the incidence of chronic rejection of allografts. The awareness that the morbidity and mortality of atherosclerotic disease may be lowered by active intervention will result in a better quality of life for transplant recipients. PMID:9497947

  18. Myelofibrosis 2012: it’s complicated

    PubMed Central

    Hubbeling, Harper G.; Frank, Dale M.

    2012-01-01

    Major advances in myeloproliferative neoplasms in the last decade have cast light on their complexity. The identification of JAK2V617F briefly promised a unifying mechanism of pathogenesis with a single pathway that could be efficiently targeted. Instead, there have been major advances in understanding acquired and background genetic and epigenetic contributors to this group of disorders, with refined risk prediction models and experimental therapeutics that have provided a more nuanced model of disease. In aggregate these observations likely explain the heterogeneity of these disorders and their generally unpredictable response to therapy. Molecular studies, beginning with the identification of JAK2V617F, have led to a concept of MPN subtypes existing on a continuum, and additional discoveries such as TET2 and EZH2 mutations have provided the molecular underpinnings to begin to explain overlapping phenotypes in myeloid malignancies more generally. In many ways the pace of molecular discovery is outstripping our ability to integrate these observations into clinical care, both in terms of molecular diagnostics and medical decision making. This review will attempt to summarize, within a clinical context, our evolving understanding of myeloproliferative neoplasms. It focuses on biology, histopathology, prognostic scoring systems, stem cell transplantation as well as selected clinical/preclinical therapeutic observations. PMID:23556120

  19. POST TRAUMATIC HYPERACTIVE DELIRIUM

    PubMed Central

    Sabhesan, S.; Natarajan, M.

    1990-01-01

    SUMMMARY Hyperactive delirium following head injury is a common problem during the early recovery phase. Twenty-nine patients who evinced hyperactive delirium were prospectively followed up during; their stay In the hospital. Compared with controls, alcohol dependence was significantly more among these patients. Occurrence of delirium was related to the generalized cerebral disturbances; due to diffuse damage in acceleration injuries and due to metabolic or post-seizure disturbances in contact injuries. Follow-up of these patients showed that psychiatric problems were more common among them. PMID:21927482

  20. Post traumatic hyperactive delirium.

    PubMed

    Sabhesan, S; Natarajan, M

    1990-10-01

    Hyperactive delirium following head injury is a common problem during the early recovery phase. Twenty-nine patients who evinced hyperactive delirium were prospectively followed up during; their stay In the hospital. Compared with controls, alcohol dependence was significantly more among these patients. Occurrence of delirium was related to the generalized cerebral disturbances; due to diffuse damage in acceleration injuries and due to metabolic or post-seizure disturbances in contact injuries. Follow-up of these patients showed that psychiatric problems were more common among them. PMID:21927482

  1. [Post Stroke Dementia].

    PubMed

    Ihara, Masafumi

    2016-07-01

    Post-stroke dementia (PSD) is a clinical entity that encompasses all types of dementia following an index stroke. Current evidence suggests that 25-30% of ischemic stroke survivors develop immediate or delayed vascular cognitive impairment or vascular dementia. The type of stroke can be either ischemic, hemorrhagic or hypoperfusive. There are multiple risk factors for PSD including older age, family history, genetic variants, low educational status, vascular comorbidities, prior transient ischemic attack or recurrent stroke and depressive illness. Pre-stroke dementia refers to the occurrence of cognitive impairment before the index stroke, which may be caused by a vascular burden as well as insidious neurodegenerative changes. Neuroimaging determinants of dementia after stroke include silent brain infarcts, white matter changes, lacunar infarcts and medial temporal lobe atrophy. Published clinical trials have not been promising and there is little information on whether PSD can be prevented using pharmacological agents. Control of vascular disease risk and prevention of recurrent strokes are key to reducing the burden of cognitive decline and post-stroke dementia. Modern imaging and analysis techniques will help to elucidate the mechanism of PSD and establish better treatment. PMID:27395459

  2. Post retention and post/core shear bond strength of four post systems.

    PubMed

    Stockton, L W; Williams, P T; Clarke, C T

    2000-01-01

    As clinicians we continue to search for a post system which will give us maximum retention while maximizing resistance to root fracture. The introduction of several new post systems, with claims of high retentive and resistance to root fracture values, require that independent studies be performed to evaluate these claims. This study tested the tensile and shear dislodgment forces of four post designs that were luted into roots 10 mm apical of the CEJ. The Para Post Plus (P1) is a parallel-sided, passive design; the Para Post XT (P2) is a combination active/passive design; the Flexi-Post (F1) and the Flexi-Flange (F2) are active post designs. All systems tested were stainless steel. This study compared the test results of the four post designs for tensile and shear dislodgment. All mounted samples were loaded in tension until failure occurred. The tensile load was applied parallel to the long axis of the root, while the shear load was applied at 450 to the long axis of the root. The Flexi-Post (F1) was significantly different from the other three in the tensile test, however, the Para Post XT (P2) was significantly different to the other three in the shear test and had a better probability for survival in the Kaplan-Meier survival function test. Based on the results of this study, our recommendation is for the Para Post XT (P2). PMID:11203854

  3. Isolated post resonator mesogyroscope

    NASA Technical Reports Server (NTRS)

    Challoner, Dorian; Peay, Chris; Wellman, Joanne; Shcheglov, Kirill; Hayworth, Ken; Wiberg, Dean; Yee, Karl; Sipppola, Clayton

    2004-01-01

    A new symmetric vibratory gyroscope principle has been devised in which a central post proof mass is counter-rocked against an outer sensing plate such that the motion is isolated from the gyroscope case. Prototype gyroscopes have been designed and fabricated with micromachined silicon at mesoscale (20-cm resonator width), vs. microscale (e.g., 2-mm resonator width) to achieve higher sensitivity and machined precision. This novel mesogyro design arose out of an ongoing technical cooperation between JPL and Boeing begun in 1997 to advance the design of micro-inertial sensors for low-cost space applications. This paper describes the theory of operation of the mesogyro and relationships with other vibratory gyroscopes, the mechanical design, closed loop electronics design, bulk silicon fabrication and packaged gyroscope assembly and test methods. The initial packaged prototype test results are reported for what is believed to be the first silicon mesogyroscope.

  4. Post dengue neurological complication.

    PubMed

    Hasliza, A H; Tohid, H; Loh, K Y; Santhi, P

    2015-01-01

    Dengue infection is highly endemic in many tropical countries including Malaysia. However, neurological complications arising from dengue infection is not common; Gullain-Barre syndrome (GBS) is one of these infrequent complications. In this paper, we have reported a case in which a 39-year-old woman presented with a neurological complication of dengue infection without typical symptoms and signs of dengue fever. She had a history of acute gastroenteritis (AGE) followed by an upper respiratory tract infection (URTI) weeks prior to her presentation rendering GBS secondary to the post viral URTI and AGE as the most likely diagnosis. Presence of thrombocytopenia was the only clue for dengue in this case. PMID:27099661

  5. Post traumatic stress disorder.

    PubMed

    Tiller, J; Kyrios, M; Bennett, P

    1996-10-01

    Post traumatic stress disorder (PTSD) occurs after a person has been exposed to a traumatic event involving actual or threatened death, and has responded with intense fear or helplessness. The event is then persistently re-experienced. The person avoids stimuli associated with the trauma and experiences a numbing of general responsiveness. Symptoms of increased arousal can occur as well as depression and anxiety. PTSD causes clinically significant distress or impairment in social, occupational, or other important areas of functioning. The general practitioner is uniquely placed to identify PTSD and can have a key role in treatment. Cognitive behavioural treatment is a central therapeutic approach and can be carried out in general practice. The issues are to counteract the physiological components, expose the patient to the feared situation and help the patient to relearn that the stimuli are not necessarily associated with danger or threat. Repeated brief consultations over time can facilitate this process. PMID:8936738

  6. Post-stroke depression.

    PubMed

    Gaete, Jorge Moncayo; Bogousslavsky, Julien

    2008-01-01

    Post-stroke depression (PSD) is among the most common emotional disorders afflicting stroke sufferers. Approximately one third of stroke survivors experience an early or later onset of depression. PSD impedes the rehabilitation and recovery process, jeopardizes quality of life and increases mortality. Diagnosis of PSD is challenging in the acute and chronic aftermath. Therefore, it often remains unrecognized and/or undertreated. The interaction between depression and stroke is very complex and the pathophysiological mechanisms have not as yet been fully elucidated, although an interaction between anatomical and psychosocial factors may be important in PSD development. Neurochemical changes and clinical findings are similar to endogenous depression. PSD is potentially treatable, although no conclusive benefits of antidepressant agents and nonpharmacological interventions have been observed. The efficacy of preventive strategies in PSD remains essentially undetermined. PMID:18088202

  7. Post-16 update

    NASA Astrophysics Data System (ADS)

    1999-01-01

    Post-16 Initiative logo This is the first of a regular series of contributions from the Institute's Post-16 Initiative. The Initiative is taking a hard and searching look at the physics taught in schools and colleges from age 16 to age 19. To start with, it is responding to Government initiatives, but hopes to encourage and stimulate good practice in physics teaching on a longer time scale than can be afforded in making responses to current developments. Here Jon Ogborn writes about what AS courses need to be, while Peter Campbell gives his thoughts about teaching matter. Advanced Subsidiary physics: what should it be? From September 2000 all A-levels will be new. Students can take the first Advanced Subsidiary (AS) year and stop there - or decide to go on. In the Institute of Physics post-16 Initiative, we have been thinking how to provide a satisfying one-year experience of physics at the new AS level, and what it should achieve. The students will decide. So the AS course must give a decent picture of what physics is, what it offers for their futures, what interests it can satisfy. That all says breadth, with enough depth to see what is in store later. And this sounds like the right recipe for someone who is taking a single AS year of physics to broaden their A-level experience. It must also be attractive. A way forward is shown by the Salters - Horners course, attracting interest through leading from applications. Why does that work? It gives physics a story to tell, into which ideas fit and make sense. Our own new A-level, Advancing Physics, must also have interesting stories to tell, which must in addition build up an honest picture of physics. An example: teach electric circuits through modern sensing devices. Sensor instrumentation is a key activity of physicists, full of new ideas, but also simple. It makes essential use of circuits such as the potential divider. Practical work gets better things to do than checking the equation for resistors in parallel

  8. Post-16 update

    NASA Astrophysics Data System (ADS)

    1999-07-01

    (post16) Faces of Physics To study a physics course post-16 is take out an option on your future. But physics itself is very varied, and so is what you might do with it. It seems right that post-16 physics courses reflect important aspects of this variety. Physics varies with why people do it. As reliable knowledge, physics is often essential to making things happen. This is physics as feeding into technology, and quite often feeding off technology. The human urge here is the urge to create things that work. It drives individual inventors; it drives large teams in multinational companies. At the opposite end of this spectrum is physics driven by curiosity, by the urge to find out. The stock examples are the grand discoveries from the expansion of the universe to the discovery of the nucleus of atoms. But the physicist's curiosity is often on a more detailed, even finicky scale: how exactly do the molecules of this polymer respond to stress?; just how do ions implanted in this material modify its conductivity? It is clear to me that a decent post-16 physics course must respect and reflect both. This is by no means a matter of `basic laws and their applications'. It is a matter of recognizing two fundamental interests, in doing and in explaining, and of recognizing that they are at once closely interdependent and worlds apart. Ideas in physics are also not of one kind. One opposition is the idea of describing Nature in terms of deterministic physical laws, as against describing Nature as the predictable outcome of probabilistic behaviour `underneath'. The first has gripped the Western imagination since at least the time of Descartes. The second has increasingly come to the fore, especially in thermodynamics with the idea that we can only make processes work by fixing the circumstances so that uncaring atoms and molecules happen by chance to do what we want. Now in quantum theory both ideas - determinism and randomness - co-exist. Post-16 physics courses are not in

  9. NEWS: Post-16 update

    NASA Astrophysics Data System (ADS)

    Campbell, Peter

    2000-07-01

    post16.gif As a teacher of physics it is very easy to become preoccupied with particulars of courses, or topics or even single concepts. Concerned with imminent student audiences and desired learning outcomes, the daily challenge is to summon satisfactory teaching approaches and resources for the job at hand. For the conscientious teacher, assessment outcomes may too often seem a judgment on our own efforts rather than those of our students. From time to time we may step back and think bigger, for example while planning a recruitment event, or while away from work on holiday. We may be successful locally. But why, at a time when books and television documentaries popularizing science have a large following, has physics education been facing declining numbers? Many recognize that physics has an essential contribution to make to the training of science or engineering specialists, but we know that it is also important for the skilled worker, the informed citizen and, in fact, for anyone trying to make sense of the world. So what are the best ways forward for post-16 physics? To make any impact on the bigger picture requires organization, thinking and meeting time among people in diverse roles: teachers and curriculum managers; university lecturers; employers and professional bodies; unitary awarding bodies; regulatory and funding agencies; and even Government. For the past few years, the Institute of Physics post-16 Initiative has created an unrivalled opportunity to address the wider issues. Its Shaping the Future booklets series was designed to stimulate informed discussion and debate, by providing background information and analysis. Taken together, the booklets should help all those concerned with physics education to understand where we are now, and why. Literally dozens of people have contributed to a review and analysis of physics education. Each booklet is a 48-page smorgasbord in A4 landscape format, containing many examples of good practice, basic but

  10. IVGEN Post Flight Analysis

    NASA Technical Reports Server (NTRS)

    Mcquillen, John; Brown, Dan; Hussey, Sam; Zoldak, John

    2014-01-01

    The Intravenous Fluid Generation (IVGEN) Experiment was a technology demonstration experiment that purified ISS potable water, mixed it with salt, and transferred it through a sterilizing filter. On-orbit performance was verified as appropriate and two 1.5 l bags of normal saline solution were returned to earth for post-flight testing by a FDA certified laboratory for compliance with United States Pharmacopiea (USP) standards. Salt concentration deviated from required values and an analysis identified probable causes. Current efforts are focused on Total Organic Content (TOC) testing, and shelf life.The Intravenous Fluid Generation (IVGEN) Experiment demonstrated the purification of ISS potable water, the mixing of the purified water with sodium chloride, and sterilization of the solution via membrane filtration. On-orbit performance was monitored where feasible and two 1.5-liter bags of normal saline solution were returned to earth for post-flight testing by a FDA-registered laboratory for compliance with United States Pharmacopeia (USP)standards [1]. Current efforts have been focused on challenge testing with identified [2] impurities (total organic-carbon), and shelf life testing. The challenge testing flowed known concentrations of contaminants through the IVGEN deionizing cartridge and membrane filters to test their effectiveness. One finding was that the filters and DI-resin themselves contribute to the contaminant load during initial startup, suggesting that the first 100 ml of fluid be discarded. Shelf life testing is ongoing and involves periodic testing of stored DI cartridges and membrane filters that are capped and sealed in hermetic packages. The testing is conducted at six month intervals measuring conductivity and endotoxins in the effluent. Currently, the packaging technique has been successfully demonstrated for one year of storage testing. The USP standards specifies that the TOC be conducted at point of generation as opposed to point of

  11. NEWS: Post-16 update

    NASA Astrophysics Data System (ADS)

    Campbell, Peter

    2000-07-01

    post16.gif As a teacher of physics it is very easy to become preoccupied with particulars of courses, or topics or even single concepts. Concerned with imminent student audiences and desired learning outcomes, the daily challenge is to summon satisfactory teaching approaches and resources for the job at hand. For the conscientious teacher, assessment outcomes may too often seem a judgment on our own efforts rather than those of our students. From time to time we may step back and think bigger, for example while planning a recruitment event, or while away from work on holiday. We may be successful locally. But why, at a time when books and television documentaries popularizing science have a large following, has physics education been facing declining numbers? Many recognize that physics has an essential contribution to make to the training of science or engineering specialists, but we know that it is also important for the skilled worker, the informed citizen and, in fact, for anyone trying to make sense of the world. So what are the best ways forward for post-16 physics? To make any impact on the bigger picture requires organization, thinking and meeting time among people in diverse roles: teachers and curriculum managers; university lecturers; employers and professional bodies; unitary awarding bodies; regulatory and funding agencies; and even Government. For the past few years, the Institute of Physics post-16 Initiative has created an unrivalled opportunity to address the wider issues. Its Shaping the Future booklets series was designed to stimulate informed discussion and debate, by providing background information and analysis. Taken together, the booklets should help all those concerned with physics education to understand where we are now, and why. Literally dozens of people have contributed to a review and analysis of physics education. Each booklet is a 48-page smorgasbord in A4 landscape format, containing many examples of good practice, basic but

  12. Nuclear Power - Post Fukushima

    NASA Astrophysics Data System (ADS)

    Reyes, Jose, Jr.

    2011-10-01

    The extreme events that led to the prolonged power outage at the Fukushima Daiicchi nuclear plant have highlighted the importance of assuring a means for stable long term cooling of the nuclear fuel and containment following a complete station blackout. Legislative bodies, regulatory agencies and industry are drawing lessons from those events and considering what changes, if any, are needed to nuclear power, post Fukushima. The enhanced safety of a new class of reactor designed by NuScale Power is drawing significant attention in light of the Fukushima events. During normal operation, each NuScale containment is fully immersed in a water-filled stainless steel lined concrete pool that resides underground. The pool, housed in a Seismic Category I building, is large enough to provided 30 days of core and containment cooling without adding water. After 30 days, the decay heat generations coupled with thermal radiation heat transfer is completely adequate to remove core decay heat for an unlimited period of time. These passive power systems can perform their function without requiring an external supply of water of power. An assessment of the NuScale passive systems is being performed through a comprehensive test program that includes the NuScale integral system test facility at Oregon State University

  13. Redefining Post-Secondary Education

    ERIC Educational Resources Information Center

    Turpin, David H.

    2005-01-01

    For at least a brief period of time, the release of Bob Rae's review of post-secondary education in Ontario served to focus public attention on the importance of post-secondary education not only in Ontario, but across Canada. This article elaborates further on Rae's review which stresses the crucial importance of the higher studies and recommends…

  14. Post-16 Science in England

    ERIC Educational Resources Information Center

    Swinscoe, David

    2012-01-01

    Science education at post-16 has had a high profile recently. Increasing the quality and quantity of STEM education is seen as a route to economic prosperity for both the individual and the nation. The post-16 sector is being encouraged to produce more STEM undergraduates and more STEM-skilled entrants to the industry with an emphasis on…

  15. NEWS: Post-16 update

    NASA Astrophysics Data System (ADS)

    1999-05-01

    (post16) Making physics connect Doesn't Melvyn Bragg do a wonderful job, engaging both scientists and artists in sensitive discussion on Radio 4 about their methods and their purposes? But every week teachers have the chance to show their students that physics is a way of seeing the world that is well-connected with other aspects of knowledge and culture. The stakes are high: students who fail to appreciate this generally choose not to study the subject beyond GCSE. Most students find our preoccupation with technical detail off-putting. Accepting that we have a syllabus to cover, it's still a question of balance. In our teaching we should aim for variety in order to find ways to connect with every student's interests. Also, we can show that we (the nearest embodiment of a physicist some students will experience) are multidimensional and so fully human. Most important, teachers need flexibility to both encourage and respond to student comment and questions. The first booklet in the discussion series Shaping the Future takes up these themes. Rich in ideas for both immediate use and the longer term, it aims to stimulate debate and improve teaching. Copies cost £5.50 including postage and are available from Ingrid Ebeyer, Post-16 Initiative, Institute of Physics, 76 Portland Place, London W1N 3DH. How far is it? This question is asked in many family cars and school minibuses at the start of a journey, and answered by most in terms of hours and minutes rather than miles. What a good idea for introducing a social and historical perspective to a lesson on distance, velocity and time. How far can you actually get in a day? What is the range of human activity? Walking for eight hours will get many people about 25 miles. A pack horse will progress at much the same rate, but fast riding or a coach and team of horses will get further. Motorway driving (when the cones are on holiday) would take you nearly 500 miles. The 05.15 am train from Penzance arrives in Inverness at 7

  16. Post-16 update

    NASA Astrophysics Data System (ADS)

    1999-11-01

    (Post-16 Initiative) Engineering Physics? Many A-level physics students do not go on to study physics. For them physics is a support subject, either just for fun or just for the grade. Where physics is a lead subject some students go on to study physics but many more go on to study engineering. So can we deliberately give some aspects of an A-level course an engineering flavour? Electromagnetism would seem a good place to start. There is a clear `physics' route into this topic, a microscopic forces and fields view of the situation. But do our students really need to look at it this way? All electromagnetic machines are linked magnetic and electric circuits. The design idea is to link these circuits as closely as possible. The electric circuits must be as good as possible, with a high conductivity. The magnetic circuits must be as good as possible, with high permeance. Conductivity depends on area/length. So does permeance. The goodness of an electromagnetic machine (how good it is at its job, which is linking electric and magnetic circuits) scales as the square of its linear dimensions. That means small electromagnetic machines are harder to make, and so the very smallest nanomotors are electrostatic. None of this is new, but many teachers are uncomfortable with it. We are thinking like physicists. Many of our students are not. They deserve us to take the trouble every now and again to encourage them to think a bit differently about a topic, to look at practical ways of discussing design and to give their course an engineering flavour. Philip Britton Coursework in A-level Physics The criteria for the new AS and A-levels have provided the teams developing the specifications with an opportunity to think creatively about how internal assessment is used within post-16 physics courses. Teachers may be concerned that allowing 30% of the marks to be internally assessed will create a burden for them. However, it is possible to look at this in a much more positive light

  17. Post-herpetic neuralgia

    PubMed Central

    Tontodonati, Monica; Ursini, Tamara; Polilli, Ennio; Vadini, Francesco; Di Masi, Francesco; Volpone, Damiano; Parruti, Giustino

    2012-01-01

    Background In spite of the large body of evidence available in the literature, definition and treatment of Post-Herpetic Neuralgia (PHN) are still lacking a consistent and universally recognized standardization. Furthermore, many issues concerning diagnosis, prediction and prevention of PHN need to be clarified in view of recent contributions. Objectives To assess whether PHN may be better defined, predicted, treated and prevented in light of recent data, and whether available alternative or adjunctive therapies may improve pain relief in treatment recalcitrant PHN. Methods Systematic reviews, meta-analyses, randomized controlled trials, cohort studies and protocols were searched; the search sources included PubMed, Cochrane Library, NICE, and DARE. More than 130 papers were selected and evaluated. Results Diagnosis of PHN is essentially clinical, but it can be improved by resorting to the many tools available, including some practical and accessible questionnaires. Prediction of PHN can be now much more accurate, taking into consideration a few well validated clinical and anamnestic variables. Treatment of PHN is presently based on a well characterized array of drugs and drug associations, including, among others, tricyclic antidepressants, gabapentinoids, opioids and many topical formulations. It is still unsatisfactory, however, in a substantial proportion of patients, especially those with many comorbidities and intense pain at herpes zoster (HZ) presentation, so that this frequent complication of HZ still strongly impacts on the quality of life of affected patients. Conclusion Further efforts are needed to improve the management of PHN. Potentially relevant interventions may include early antiviral therapy of acute HZ, prevention of HZ by adult vaccination, as well as new therapeutic approaches for patients experiencing PHN. PMID:23109810

  18. Reviewing Canadian Post-Secondary Education: Post-Secondary Education Policy in Post-Industrial Canada

    ERIC Educational Resources Information Center

    Kirby, Dale

    2007-01-01

    Since 2004, a number of Canadian provinces have initiated comprehensive reviews of their respective public post-secondary education systems. This paper examines the ways in which these provincial post-secondary education reviews are consistent with the pervasive influence of economic globalization on higher education and a more market-driven and…

  19. Post-16 update

    NASA Astrophysics Data System (ADS)

    1999-03-01

    Post-16 Initiative logo Physics in Mathematical Mood Later this year, as part of the post-16 initiative of the Institute of Physics, a booklet with the above title will be published. In draft form, the booklet was discussed at the ASE conference in January. Some of the issues raised are briefly set out here. If you have any views to contribute, please write to Simon Carson at the Institute of Physics or e-mail simon.carson@physics.org. A mathematical view of the world is intrinsically a part of physics and therefore physics should be studied in an appropriately mathematical way. However, we all know that, to some students at least, mathematics proves to be a stumbling block rather than a powerful aid to understanding. So how can we help? Realizing that as physics teachers we need to deliver the mathematics necessary to an understanding of our subject is a start. Its corollary is that we need to find the space within the physics core. We may wish to use supplementary courses such as AS mathematics or QCA's new free-standing mathematics units, but requiring additional courses as a prerequisite to a study of A-level physics may deter students. Teaching the mathematics in context may aid understanding but we also must ensure that techniques are seen in a variety of contexts and that at some point the tool is abstracted from the background. As teachers we need to be aware of the very basic mathematical difficulties that students bring with them: the use of calculators, standard form, simple algebraic manipulation, for example. Mathematical arguments need to be developed fully and carefully. Encouraging cooperation and discussion between students may help the less able to understand and the more able to appreciate and develop their own understanding through making explicit their reasoning by explaining it to others. And what of new technology? Software tools allow students to develop their understanding about graphs, for example, enabling them to investigate the

  20. 75 FR 4039 - Proposed Posting, Posting, and Deposting of Stockyards

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-01-26

    ... the Federal Register (74 FR 17945-17947) of our proposal to post these 20 stockyards. Since we... location CA-193 Westside Auction Yard, Newman, California. AZ-117 Robertson Horse Sales, Benson,...

  1. Post-16 update

    NASA Astrophysics Data System (ADS)

    1999-03-01

    Post-16 Initiative logo Physics in Mathematical Mood Later this year, as part of the post-16 initiative of the Institute of Physics, a booklet with the above title will be published. In draft form, the booklet was discussed at the ASE conference in January. Some of the issues raised are briefly set out here. If you have any views to contribute, please write to Simon Carson at the Institute of Physics or e-mail simon.carson@physics.org. A mathematical view of the world is intrinsically a part of physics and therefore physics should be studied in an appropriately mathematical way. However, we all know that, to some students at least, mathematics proves to be a stumbling block rather than a powerful aid to understanding. So how can we help? Realizing that as physics teachers we need to deliver the mathematics necessary to an understanding of our subject is a start. Its corollary is that we need to find the space within the physics core. We may wish to use supplementary courses such as AS mathematics or QCA's new free-standing mathematics units, but requiring additional courses as a prerequisite to a study of A-level physics may deter students. Teaching the mathematics in context may aid understanding but we also must ensure that techniques are seen in a variety of contexts and that at some point the tool is abstracted from the background. As teachers we need to be aware of the very basic mathematical difficulties that students bring with them: the use of calculators, standard form, simple algebraic manipulation, for example. Mathematical arguments need to be developed fully and carefully. Encouraging cooperation and discussion between students may help the less able to understand and the more able to appreciate and develop their own understanding through making explicit their reasoning by explaining it to others. And what of new technology? Software tools allow students to develop their understanding about graphs, for example, enabling them to investigate the

  2. 32 CFR 643.120 - Post offices.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 32 National Defense 4 2012-07-01 2011-07-01 true Post offices. 643.120 Section 643.120 National... Additional Authority of Commanders § 643.120 Post offices. Title 10 U.S.C. 4779b, provides that the SA shall assign suitable space for post office purposes at military posts where post offices have been...

  3. 32 CFR 643.120 - Post offices.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 32 National Defense 4 2014-07-01 2013-07-01 true Post offices. 643.120 Section 643.120 National... Additional Authority of Commanders § 643.120 Post offices. Title 10 U.S.C. 4779b, provides that the SA shall assign suitable space for post office purposes at military posts where post offices have been...

  4. 32 CFR 643.120 - Post offices.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 4 2010-07-01 2010-07-01 true Post offices. 643.120 Section 643.120 National... Additional Authority of Commanders § 643.120 Post offices. Title 10 U.S.C. 4779b, provides that the SA shall assign suitable space for post office purposes at military posts where post offices have been...

  5. 32 CFR 643.120 - Post offices.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 32 National Defense 4 2011-07-01 2011-07-01 false Post offices. 643.120 Section 643.120 National... Additional Authority of Commanders § 643.120 Post offices. Title 10 U.S.C. 4779b, provides that the SA shall assign suitable space for post office purposes at military posts where post offices have been...

  6. 32 CFR 643.120 - Post offices.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 32 National Defense 4 2013-07-01 2013-07-01 false Post offices. 643.120 Section 643.120 National... Additional Authority of Commanders § 643.120 Post offices. Title 10 U.S.C. 4779b, provides that the SA shall assign suitable space for post office purposes at military posts where post offices have been...

  7. Post-Traumatic Stress Disorder

    MedlinePlus

    ... PTSD include violent personal assaults, natural or human-caused disasters, accidents, or military combat. For Consumers General Information Post-Traumatic Stress Disorder ( NIMH ) Anxiety Information Stress Information Depression Information St. John's Wort Information See more Research ...

  8. Post-Traumatic Stress Disorder

    MedlinePlus

    ... Physician September 01, 2000, http://www.aafp.org/afp/20000901/1035.html) Post-traumatic Stress Reactions Following ... Physician August 01, 1999, http://www.aafp.org/afp/990800ap/524.html) Written by familydoctor.org editorial ...

  9. [Post-mortem microbiology analysis].

    PubMed

    Fernández-Rodríguez, Amparo; Alberola, Juan; Cohen, Marta Cecilia

    2013-12-01

    Post-mortem microbiology is useful in both clinical and forensic autopsies, and allows a suspected infection to be confirmed. Indeed, it is routinely applied to donor studies in the clinical setting, as well as in sudden and unexpected death in the forensic field. Implementation of specific sampling techniques in autopsy can minimize the possibility of contamination, making interpretation of the results easier. Specific interpretation criteria for post-mortem cultures, the use of molecular diagnosis, and its fusion with molecular biology and histopathology have led to post-mortem microbiology playing a major role in autopsy. Multidisciplinary work involving microbiologists, pathologists, and forensic physicians will help to improve the achievements of post-mortem microbiology, prevent infectious diseases, and contribute to a healthier population. PMID:23195835

  10. Post-traumatic stress disorder

    MedlinePlus

    Post-traumatic stress disorder (PTSD) is a type of anxiety disorder . It can occur after you have gone through an extreme ... Normally, after the event, the body recovers. The stress hormones and chemicals the body releases due to ...

  11. [Management of post partum haemorrhage].

    PubMed

    Csorba, Roland

    2012-04-29

    Primary post partum haemorrhage is the most common form of major obstetric haemorrhage. The traditional definition of primary post partum haemorrhage is the loss of 500 ml or more of blood from the genital tract within 24 hours of the birth of a baby. Post partum haemorrhage can be minor (500-1000 ml) or major (more than 1000 ml). Major could be divided to moderate (1000-2000 ml) or severe (more than 2000 ml). The recommendations in this article apply to women experiencing primary post partum haemorrhage of 500 ml or more. Secondary post partum haemorrhage is defined as abnormal or excessive bleeding from the birth canal between 24 hours and 12 weeks postnatally. The main causes of the secondary form are: inflammations (endometritis), placental tissue retention, inadequate involution of the uterus and malignancy. Because of its importance as a leading cause of maternal morbidity and mortality, obstetric haemorrhage must be considered as a priority topic. According to the tragic and dramatic outcomes of this morbidity, and to the fact that most cases of post partum haemorrhage have no identifiable risk factors, the practical obstetricians should be aware of the accurate diagnosis and management of this illness. PMID:22543219

  12. Post-16 update

    NASA Astrophysics Data System (ADS)

    1999-09-01

    Institute of Physics post-16 initiative, shaping the future Physics education based in IT - sorry ICT! Which, of course, makes for a nifty headline, but as is so often the case with neat slogans, little else. Two formative questions: What, in another decade, will the government of the day call `What you lot should be doing with computers'? and What, of the many things that currently exercise our intellects, will there be anything special to say about in a decade, concerning the use of computers in the teaching of physics? Advancing Physics represents some attempts to come to grips with the second of the two questions above. The first is left to a higher wisdom. In thinking about learning, what can we do with the huge processing power, increasingly available in smaller and less obtrusive packages? What will we do that helps people learn physics, both tomorrow and in 2009? Here are a few suggestions based on development work so far. Wide, reliable and shared access to well ordered learning resources. We have created a CD-ROM, with versions for both student and teacher, that provides a wide range of resources. These do not teach, but do provide. A commitment to allowing a course to evolve and adapt. Electronic publication puts the costs into origination, and not into publication and distribution. A website allows for the community of users to contribute. E-mail networks support individuals and propagate good practice. You can create and explore your own microworlds. The interactive nature of models, and the crafted relationships between the models and the natural world give an insight into the creative imaginary worlds of the physicist. The unreasonable, but pleasurable, success of mathematics in describing the natural world can come to the fore. Measurements that were not possible before are now possible. What was previously indirect, and inaccessible, now becomes a direct measurement, making relationships transparent in new and fruitful ways. The dichotomy between

  13. Post-mortem clinical pharmacology

    PubMed Central

    Ferner, R E

    2008-01-01

    Clinical pharmacology assumes that deductions can be made about the concentrations of drugs from a knowledge of the pharmacokinetic parameters in an individual; and that the effects are related to the measured concentration. Post-mortem changes render the assumptions of clinical pharmacology largely invalid, and make the interpretation of concentrations measured in post-mortem samples difficult or impossible. Qualitative tests can show the presence of substances that were not present in life, and can fail to detect substances that led to death. Quantitative analysis is subject to error in itself, and because post-mortem concentrations vary in largely unpredictable ways with the site and time of sampling, as a result of the phenomenon of post-mortem redistribution. Consequently, compilations of ‘lethal concentrations’ are misleading. There is a lack of adequate studies of the true relationship between fatal events and the concentrations that can be measured subsequently, but without such studies, clinical pharmacologists and others should be wary of interpreting post-mortem measurements. PMID:18637886

  14. Nitric oxide scavenging by cell-free hemoglobin may be a primary factor determining hypertension in polycythemic patients.

    PubMed

    Rusak, T; Misztal, T; Piszcz, J; Tomasiak, M

    2014-02-01

    We tested the hypothesis that hypertension associated with polycythemia vera (PV) may be related to hemoglobin released from erythrocytes (cell-free hemoglobin, fHb). We assessed hematocrit, mean arterial pressure (MAP), blood viscosity, and the level of fHb and nitrite/nitrate (NOx) in the plasma of 73 PV patients and 38 healthy controls. The effect of isovolemic erythrocytapheresis (ECP) on the considered parameters was also studied. From the whole group of PV patients a subset of subjects with normal (normotensive patients, n = 16) and elevated MAP (hypertensive patients, n = 57) can be subtracted. It was found that in comparison with healthy controls, PV patients have significantly (p ≤ 0.01) elevated Hct (0.567 vs. 0.422), blood viscosity (5.45 vs. 3.56 cP), MAP (106.8 vs. 93.8 mmHg), plasma fHb (9.7 vs. 2.8 mg/dL), and NOx levels (34.1 vs. 27.5 μM). Compared with normotensive patients, hypertensive PV patients demonstrated a higher rise in fHb (10.2 vs. 8.0) and plasma NOx levels (35.8 vs. 31.0). In PV patients, fHb positively correlates with MAP (r = 0.489), NOx levels (r = 0.461), hematocrit (r = 0.428), and viscosity (r = 0.393). Blood viscosity positively correlated with hematocrit (r = 0.894), but not with other considered parameters. In PV patients MAP poorly correlated with hematocrit, whereas the correlation between MAP and NOx altered from - 0.325 (healthy control) to + 0.268 (PV patients). ECP procedure was associated with a significant (p < 0.01) reduction of hematocrit, fHb, blood viscosity, and MAP. In the normotensive subgroup of PV patients the ECP procedure did not affect MAP. It can be concluded that accelerated scavenging of nitric oxide by fHb rather than high Hct may be a key factor determining the development of hypertension in PV patients. PMID:24180690

  15. Post-Newtonian gravitational bremsstrahlung

    NASA Technical Reports Server (NTRS)

    Turner, M.; Will, C. M.

    1977-01-01

    Formulae and numerical results are presented for the gravitational radiation emitted during a low-deflection encounter between two massive bodies. Results are valid through post-Newtonian order within general relativity. The gravitational waveform, the total luminosity and total emitted energy, the angular distribution of emitted energy, and the frequency spectrum are discussed in detail. A method boosting the accuracy of these quantities to post Newtonian order is also presented. A numerical comparison of results with those of Peters, and of Kovacs and Thorne shows that the post Newtonian method is reliable to better than 0.1 percent at v = 0.1 c, to a few percent at v = 0.35 c, and to 10 to 20 percent at v = 0.5 c.

  16. RCRA post-closure permits

    SciTech Connect

    Not Available

    1993-05-01

    The Resource Conservation and Recovery Act (RCRA) requires that hazardous waste management facilities operate in accordance with permits granted by the US Environmental Protection Agency (EPA) or a State authorized to carry out the RCRA Subtitle C program. Several categories of permits (including treatment, storage, and disposal permits; research, development, and demonstration permits; post-closure permits; emergency permits; permits-by-rule; and trial burn and land treatment demonstration permits) are issued under the RCRA Subtitle C program. This Information Brief focuses on post-closure permitting requirements under 40 CFR 270.1(c).

  17. 39 CFR 241.1 - Post offices.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 39 Postal Service 1 2013-07-01 2013-07-01 false Post offices. 241.1 Section 241.1 Postal Service... DISCONTINUANCE § 241.1 Post offices. Post Offices are established and maintained at locations deemed necessary to... geographic boundaries. A Post Office may be operated or staffed by a postmaster or by another type of...

  18. 39 CFR 241.1 - Post offices.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 39 Postal Service 1 2012-07-01 2012-07-01 false Post offices. 241.1 Section 241.1 Postal Service... DISCONTINUANCE § 241.1 Post offices. (a) Establishment. Post Offices are established and maintained at locations... within specified geographic boundaries. A Post Office may be operated or staffed by a postmaster or...

  19. 39 CFR 241.1 - Post offices.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 39 Postal Service 1 2014-07-01 2014-07-01 false Post offices. 241.1 Section 241.1 Postal Service... DISCONTINUANCE § 241.1 Post offices. Post Offices are established and maintained at locations deemed necessary to... geographic boundaries. A Post Office may be operated or staffed by a postmaster or by another type of...

  20. Reconsidering Post-Traumatic Stress

    ERIC Educational Resources Information Center

    Berman, Dene S.; Davis-Berman, Jennifer

    2005-01-01

    This article serves to challenge the prevailing wisdom that suggests that most trauma is followed by post-traumatic stress disorder (PTSD), and is best treated with critical incident stress debriefing (CISD). Instead, recent evidence suggests that many individuals exposed to stress do not experience stress responses. Even those who do, however,…

  1. Chaos Theory and Post Modernism

    ERIC Educational Resources Information Center

    Snell, Joel

    2009-01-01

    Chaos theory is often associated with post modernism. However, one may make the point that both terms are misunderstood. The point of this article is to define both terms and indicate their relationship. Description: Chaos theory is associated with a definition of a theory dealing with variables (butterflies) that are not directly related to a…

  2. Post High School Plans Survey.

    ERIC Educational Resources Information Center

    Muskingum Area Technical Coll., Zanesville, OH.

    This survey investigated the immediate after-high school plans of high school juniors, with a special emphasis on post-secondary education intentions. The survey included the responses of 1,064 students from 12 high schools. Forty-nine percent of the respondents indicated that they planned to attend a four-year college or university, 18 percent…

  3. Job Posting: An Industry Survey

    ERIC Educational Resources Information Center

    Dahl, Dave R.; Pinto, Patrick R.

    1977-01-01

    Reports a survey to determine practices among metalworking firms in Minnesota covering such topics as whether or not the company had a formal or informal job posting system, the actual mechanics of the system, union influence on its design, feedback to unsuccessful job bidders, and current employee acceptance of the system. Recommendations are…

  4. Pair take top science posts

    NASA Astrophysics Data System (ADS)

    Pockley, Peter

    2008-11-01

    Australia's science minister Kim Carr has appointed physical scientists to key posts. Penny Sackett, an astronomer, takes over as the government's chief scientist this month, while in January geologist Megan Clark will become chief executive of the Commonwealth Scientific and Industrial Research Organisation (CSIRO), the county's largest research agency. Both five-year appointments have been welcomed by researchers.

  5. Issues in post-literacy

    NASA Astrophysics Data System (ADS)

    Dave, Ravindra H.; Ouane, Adama; Sutton, Peter

    1989-12-01

    While school enrolments have been rising, the absolute number of illiterates in the world has grown too. Eradication of adult illiteracy and universalization of primary education are hindered by high drop-out in schools and relapse into illiteracy among adults. Post-literacy programmes seek to stop this reversal by ensuring retention, application and continuation of literacy skills. The Unesco Institute for Education (UIE) has been researching and promoting post-literacy strategies since 1980, but finds that most projects do not include provision for post-literacy from the outset, despite the evident need. Those programmes which have been mounted use a variety of strategies, which UIE has analysed in 12 categories. The exact delimitation of the post-literacy stage in the lifelong education continuum differs from project to project, and the emphasis on individual or societal advance depends on local perceptions of the goals of development. Examples are given of successful programmes, and the challenges of increasing participation and motivation, securing adequate funding, and making efficient and flexible use of institutional facilities are discussed.

  6. Tuberculosis drug discovery in the post-post-genomic era

    PubMed Central

    Lechartier, Benoit; Rybniker, Jan; Zumla, Alimuddin; Cole, Stewart T

    2014-01-01

    The expectation that genomics would result in new therapeutic interventions for infectious diseases remains unfulfilled. In the post-genomic era, the decade immediately following the availability of the genome sequence of Mycobacterium tuberculosis, tuberculosis (TB) drug discovery relied heavily on the target-based approach but this proved unsuccessful leading to a return to whole cell screening. Genomics underpinned screening by providing knowledge and many enabling technologies, most importantly whole genome resequencing to find resistance mutations and targets, and this resulted in a selection of leads and new TB drug candidates that are reviewed here. Unexpectedly, many new targets were found to be ‘promiscuous’ as they were inhibited by a variety of different compounds. In the post-post-genomics era, more advanced technologies have been implemented and these include high-content screening, screening for inhibitors of latency, the use of conditional knock-down mutants for validated targets and siRNA screens. In addition, immunomodulation and pharmacological manipulation of host functions are being explored in an attempt to widen our therapeutic options. PMID:24401837

  7. The ISAC post-accelerator

    NASA Astrophysics Data System (ADS)

    Laxdal, R. E.; Marchetto, M.

    2014-01-01

    The acceleration chain of the ISAC facility boosts the energy of both radioactive and stable light and heavy ions for beam delivery to both a medium energy area in ISAC-I and a high energy area in ISAC-II. The post-accelerator comprises a 35.4 MHz RFQ to accelerate beams of A/q ≤ 30 from 2 keV/u to 150 keV/u and a post stripper, 106.1 MHz variable energy drift tube linac (DTL) to accelerate ions of A/q ≤ 6 to a final energy between 0.15 MeV/u to 1.5 MeV/u. A 40 MV superconducting linac further accelerates beam from 1.5 MeV/u to energies above the Coulomb barrier. All linacs operate cw to preserve beam intensity.

  8. Post-infectious disease syndrome.

    PubMed Central

    Bannister, B. A.

    1988-01-01

    Many post-infectious syndromes have been recognized in the last 50 years, some following viral infections and others closely related to bacterial disease. The occurrence of prolonged fatigue following an apparent viral illness of varying severity is also well documented. The lack of a recognizable precipitating cause and the tendency for epidemic fatigue to occur among hospital staff led many to believe that the illness may be psychogenic in origin. However, there is serological evidence that some cases may follow enterovirus infections or occasionally delayed convalescence from infectious mononucleosis. Much interesting work is currently in progress relating fatigue to persisting immunological abnormalities, and the development of molecular immunology makes this a most exciting field of research. This paper reviews the evidence for and against a definitive post-viral fatigue syndrome and examines the results of research carried out in the last 50 years. PMID:3074289

  9. Post-Lyme disease syndrome

    PubMed Central

    Dąbek, Józefa; Cieślik, Paweł

    2015-01-01

    About 10% of patients with Lyme disease continue to experience musculoskeletal pain and cognitive dysfunction after recommended antibiotic treatment. This condition is called post-Lyme disease syndrome (PLDS) or post-treatment Lyme disease syndrome. These two terms are used interchangeably. The pathogenesis of PLDS has been controversial. The hypothesis that patients with PLDS may harbor hidden reservoirs of Borrelia burgdorferi after their initial antibiotic treatment is difficult to accept. The prospective, double-blind studies contradict this point of view. Also, recently published research applying xenodiagnosis to PLDS supports the opinion that PLDS most likely has an autoimmune background. Lengthy courses of antibiotics are not justified in patients with PLDS because of the lack of benefit, and they are fraught with hazards. Most patients with PLDS recover from persistent symptoms with time. However, it can take months before they feel completely well.

  10. Leg ischemia post-varicocelectomy

    PubMed Central

    Al-Wahbi, Abdullah M; Elmoukaied, Shaza

    2016-01-01

    Varicocelectomy is the most commonly performed operation for the treatment of male infertility. Many surgical approaches are used as each of them has advantages over the other and is preferred by surgeons. Vascular injury has never been reported as a complication of varicocelectomy apart from testicular artery injury. We present a 36-year-old male who developed leg ischemia post-varicocelectomy due to common femoral artery injury. He was successfully treated by using a vein graft. PMID:27022305

  11. [Post-marketing surveillance studies].

    PubMed

    Pigeot, I; Windeler, J

    2005-05-01

    Approval of a drug on the market is typically considered as the successful endpoint of a long development phase. This often leads to reduced interest in further research for the indication approved, while in contrast the patient's as well as physician's interest in further research increases. This paper discusses the main areas of effectiveness, safety and post-marketing practice regarding sensible study types for the specific area and the potential gain of knowledge. PMID:15887069

  12. The SPOOKI post production system

    NASA Astrophysics Data System (ADS)

    Beauchemin, M.; Klasa, M.; Fortier, S.; Fortin, F.; Hardy, G.; Pelletier, L.; Edouard, S.; Archambault, B.; Yazidi, H.

    2010-09-01

    The Canadian Meteorological Centre (CMC) delivers a large number of numerical weather prediction products to the various weather offices and clients throughout Canada and abroad. The current post production system was built according to the needs and ideology of the 1980's and it is becoming obsolete with time. Its cumbersome architecture is difficult to maintain and requires a lot of human and computing resources. The "Weather Elements" section of CMC is aware of the problems associated with its maintenance in the long term and has therefore decided to review in depth the whole approach to the operational post production. The analysis of present and future needs have led to the development of an innovative concept in the operational production field inspired by the "Plug and Play" process. SPOOKI (Système de Production Orienté-Objet contennant une Kyrielle d'Informations - Object oriented production system containing a myriad of information) was created in its present form in 2007. It is based on a modular approach where each plug-in component is specialized, reusable and autonomous. These object oriented programming characteristics greatly simplify the maintenance of the system. Particular attention was also given to create a user-friendly system for novice users. An experimental version of SPOOKI is currently running in development mode and an operational one is planned to be implemented in the coming year. The poster presentation will describe SPOOKI, the future CMC operational post production system. Several examples of usage will be shown.

  13. 75 FR 78778 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-12-16

    ... informs the public that an appeal of the closing of the Holmes Mill (Kentucky) Post Office has been filed... of the closing of the Holmes Mill Post Office in Holmes Mill, Kentucky. The petition, which was...

  14. 42 CFR 124.604 - Posted notice.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... facility shall post notices, which the Secretary supplies in English and Spanish, in appropriate areas of... other than English or Spanish, the facility shall translate the notice into that language and post...

  15. 76 FR 44385 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-07-25

    ... informs the public that an appeal of the closing of the Peach Orchard, Arkansas post office has been filed... review of the closing of the Peach Orchard, Arkansas post office. The petition, which was filed...

  16. 76 FR 9056 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-02-16

    ... informs the public that an appeal of the closing of the Lincoln Branch Post Office in Mansfield, Ohio, has... for review of the closing of the Lincoln Branch Post Office in Mansfield, Ohio. The petition,...

  17. Post-Traumatic Stress Disorder (PDQ)

    MedlinePlus

    ... with post-traumatic stress need early treatment with methods that are used to treat other trauma victims. ... symptoms of post-traumatic stress. The crisis intervention method aims to relieve distress and help the patient ...

  18. Schooling in a Post-Industrial Society

    ERIC Educational Resources Information Center

    Doll, William, E. Jr.

    1978-01-01

    Explores the coming post-industrial society for its possible effects on the education-schooling syndrome we now have. Emphasizes the sociological writings of the "father" of post-industrialism, Daniel Bell. (Author/RK)

  19. 77 FR 3806 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-25

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document... Station post office in Yerington, Nevada. The first petition for review received December 28, 2011,...

  20. 76 FR 53984 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-08-30

    ... informs the public that an appeal of the closing of the Prairie Hill, Texas post office has been filed. It... for review of the Postal Service's determination to close the Prairie Hill post office in Prairie...

  1. 76 FR 59451 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-26

    ... informs the public that an appeal of the closing of the Coyote, New Mexico post office has been filed. It... Postal Service's determination to close the Coyote post office in Coyote, New Mexico. The petition was filed by Manuelita Trujillo on behalf of the Concerned Citizens of the Coyote Post Office...

  2. 49 CFR 238.213 - Corner posts.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... or its supporting car body structure. (3) Prior to or during structural deformation, each corner post... supporting car body structure. (4) Prior to or during structural deformation, the two posts in combination... deformation of either the post or its supporting car body structure. (2) For purposes of this paragraph...

  3. 49 CFR 238.213 - Corner posts.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... or its supporting car body structure. (3) Prior to or during structural deformation, each corner post... supporting car body structure. (4) Prior to or during structural deformation, the two posts in combination... deformation of either the post or its supporting car body structure. (2) For purposes of this paragraph...

  4. 49 CFR 238.213 - Corner posts.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... or its supporting car body structure. (3) Prior to or during structural deformation, each corner post... supporting car body structure. (4) Prior to or during structural deformation, the two posts in combination... deformation of either the post or its supporting car body structure. (2) For purposes of this paragraph...

  5. 49 CFR 238.213 - Corner posts.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... or its supporting car body structure. (3) Prior to or during structural deformation, each corner post... supporting car body structure. (4) Prior to or during structural deformation, the two posts in combination... deformation of either the post or its supporting car body structure. (2) For purposes of this paragraph...

  6. 49 CFR 238.213 - Corner posts.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... or its supporting car body structure. (3) Prior to or during structural deformation, each corner post... supporting car body structure. (4) Prior to or during structural deformation, the two posts in combination... deformation of either the post or its supporting car body structure. (2) For purposes of this paragraph...

  7. Post-Colonial Theory and Action Research

    ERIC Educational Resources Information Center

    Parsons, Jim B.; Harding, Kelly J.

    2011-01-01

    This essay explores connections between post-colonial theory and action research. Post-colonial theory is committed to addressing the plague of colonialism. Action research, at its core, promises to problematize uncontested "colonial" hegemonies of any form. Both post-colonial theory and action research engage dialogic, critically reflective and…

  8. 76 FR 72454 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-23

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Elmo, Missouri post office has been filed. It... received a petition for review of the Postal Service's determination to close the Elmo post office in...

  9. 76 FR 76443 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-07

    ... COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Greeley, Iowa post office has been filed. It... received a petition for review of the Postal Service's determination to close the Greeley post office...

  10. 76 FR 68232 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-03

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Ogden, Arkansas post office has been filed. It... received a petition for review of the Postal Service's determination to close the Ogden post office...

  11. 76 FR 76444 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-07

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Holland, Iowa post office has been filed. It... received a petition for review of the Postal Service's determination to close the Holland post office...

  12. 75 FR 4429 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-01-27

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Sundance, CO, post office has been filed. It... closing of the Sundance post office located in Steamboat Springs, Colorado 80487. The appeal was...

  13. 76 FR 72456 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-23

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Scottville, Illinois post office has been filed... received a petition for review of the Postal Service's determination to close the Scottville post office...

  14. 76 FR 76447 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-07

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Miller, Nebraska post office has been filed. It... received a petition for review of the Postal Service's determination to close the Miller post office...

  15. 76 FR 54511 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-01

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Lake Creek, Texas post office has been filed. It... Service's determination to close the Lake Creek post office in Lake Creek, Texas. The petitions were...

  16. 75 FR 70956 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-11-19

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Lancaster, Tennessee post office has been filed... for review of the closing of the Lancaster Post Office located in Lancaster, Tennessee. The...

  17. 76 FR 54264 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-08-31

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Enloe, Texas post office has been filed. It... Postal Service's determination to close the Enloe post office in Enloe, Texas. The petitions were...

  18. 76 FR 76451 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-07

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Nixon, Nevada post office has been filed. It... received a petition for review of the Postal Service's determination to close the Nixon post office...

  19. 76 FR 78954 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-20

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Milan, Kansas post office has been filed. It... close the Milan post office in Milan, Kansas. The petition for review was filed by Michele...

  20. 76 FR 72457 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-23

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Morgan City, Mississippi post office has been... two petitions for review of the Postal Service's determination to close the Morgan City post office...

  1. 76 FR 76445 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-07

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Mountain City, Nevada post office has been filed... for review of the Postal Service's determination to close the Mountain City post office in...

  2. 76 FR 63332 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-12

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Evansdale, Iowa post office has been filed. It... received a petition for review of the Postal Service's determination to close the Evansdale post office...

  3. 76 FR 72453 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-23

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Waverly, Washington post office has been filed. It... received a petition for review of the Postal Service's determination to close the Waverly post office...

  4. 76 FR 58058 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-19

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Meridian, New York post office has been filed. It... Postal Service's determination to close the Meridian post office in Meridian, New York. The petition...

  5. 76 FR 76446 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-07

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Home, Kansas post office has been filed. It... for review of the Postal Service's determination to close the Home post office in Home, Kansas....

  6. 77 FR 5582 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-02-03

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Balm, Florida post office has been filed. It... Commission received a petition for review of the Postal Service's determination to close the Balm post...

  7. 76 FR 76449 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-07

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Spring Dale, West Virginia post office has been... four petitions for review of the Postal Service's determination to close the Spring Dale post office...

  8. 76 FR 76448 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-07

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Viola, Idaho post office has been filed. It... for review of the Postal Service's determination to close the Viola post office in Viola, Idaho....

  9. 76 FR 80986 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-27

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the McCallsburg, Iowa post office has been filed. It... close the McCallsburg post office in McCallsburg, Iowa. The petition for review was filed by...

  10. 76 FR 55426 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-07

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Ottosen, Iowa post office has been filed. It... for review of the Postal Service's determination to close the Ottosen post office in Ottosen,...

  11. 76 FR 54265 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-08-31

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the West Elkton, Ohio post office has been filed. It... Postal Service's determination to close the West Elkton post office in West Elkton, Ohio. The...

  12. 76 FR 68231 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-03

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Ferguson, Iowa post office has been filed. It... received a petition for review of the Postal Service's determination to close the Ferguson post office...

  13. 76 FR 72458 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-23

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Pace, Mississippi post office has been filed. It... for review of the Postal Service's determination to close the Pace post office in Pace,...

  14. 76 FR 55425 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-07

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Watson, Alabama post office has been filed. It... for review of the Postal Service's determination to close the Watson post office in Watson,...

  15. 76 FR 78702 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-19

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Sherwood, Michigan post office has been filed. It... close the Sherwood post office in Sherwood, Michigan. The petition for review was filed by...

  16. 75 FR 15753 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-03-30

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Crescent Lake (Oregon)Post Office ZIP Code 97425... of the closing of the Crescent Lake Post Office, Crescent Lake, Oregon 97425. The appeal was...

  17. 76 FR 66337 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-26

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Ruth, Mississippi, post office has been filed. It... received a petition for review of the Postal Service's determination to close the Ruth post office in...

  18. 36 CFR 261.51 - Posting.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 36 Parks, Forests, and Public Property 2 2013-07-01 2013-07-01 false Posting. 261.51 Section 261.51 Parks, Forests, and Public Property FOREST SERVICE, DEPARTMENT OF AGRICULTURE PROHIBITIONS Prohibitions in Areas Designated by Order § 261.51 Posting. Posting is accomplished by: (a) Placing a copy of the order imposing each prohibition in...

  19. 10 CFR 20.1902 - Posting requirements.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... HIGH RADIATION AREA.” (d) Posting of airborne radioactivity areas. The licensee shall post each airborne radioactivity area with a conspicuous sign or signs bearing the radiation symbol and the words “CAUTION, AIRBORNE RADIOACTIVITY AREA” or “DANGER, AIRBORNE RADIOACTIVITY AREA.” (e) Posting of areas...

  20. 10 CFR 20.1902 - Posting requirements.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... HIGH RADIATION AREA.” (d) Posting of airborne radioactivity areas. The licensee shall post each airborne radioactivity area with a conspicuous sign or signs bearing the radiation symbol and the words “CAUTION, AIRBORNE RADIOACTIVITY AREA” or “DANGER, AIRBORNE RADIOACTIVITY AREA.” (e) Posting of areas...

  1. 10 CFR 20.1902 - Posting requirements.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... HIGH RADIATION AREA.” (d) Posting of airborne radioactivity areas. The licensee shall post each airborne radioactivity area with a conspicuous sign or signs bearing the radiation symbol and the words “CAUTION, AIRBORNE RADIOACTIVITY AREA” or “DANGER, AIRBORNE RADIOACTIVITY AREA.” (e) Posting of areas...

  2. 10 CFR 20.1902 - Posting requirements.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... HIGH RADIATION AREA.” (d) Posting of airborne radioactivity areas. The licensee shall post each airborne radioactivity area with a conspicuous sign or signs bearing the radiation symbol and the words “CAUTION, AIRBORNE RADIOACTIVITY AREA” or “DANGER, AIRBORNE RADIOACTIVITY AREA.” (e) Posting of areas...

  3. 10 CFR 20.1902 - Posting requirements.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... HIGH RADIATION AREA.” (d) Posting of airborne radioactivity areas. The licensee shall post each airborne radioactivity area with a conspicuous sign or signs bearing the radiation symbol and the words “CAUTION, AIRBORNE RADIOACTIVITY AREA” or “DANGER, AIRBORNE RADIOACTIVITY AREA.” (e) Posting of areas...

  4. Programs Handle PostScript Files

    NASA Technical Reports Server (NTRS)

    Choi, Diana; Yip, David

    1992-01-01

    PSTOOLS is package of four programs to interpret and format files in PostScript language. PSIRIS, PSMATRIX, and PSTEK interpret PostScript language and send graphical results to device. PSPRETTY formats PostScript files by appropriately indenting procedures and code delimited by "saves" and "restores". Written in C.

  5. 36 CFR 261.51 - Posting.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 36 Parks, Forests, and Public Property 2 2012-07-01 2012-07-01 false Posting. 261.51 Section 261.51 Parks, Forests, and Public Property FOREST SERVICE, DEPARTMENT OF AGRICULTURE PROHIBITIONS Prohibitions in Areas Designated by Order § 261.51 Posting. Posting is accomplished by: (a) Placing a copy...

  6. Post-Process "Pedagogy": A Philosophical Exercise.

    ERIC Educational Resources Information Center

    Breuch, Lee-Ann M. Kastman

    2002-01-01

    Notes post-process theories of composition instruction suggest that process is no longer an adequate explanation of the writing act. Explains how post-process theory can contribute to composition pedagogy. Argues that post-process theory encourages educators to reexamine the definition of writing as an activity rather than a body of knowledge,…

  7. 76 FR 60947 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-30

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Jordanville, New York post office has been filed... petition for review of the Postal Service's determination to close the Jordanville post office...

  8. 76 FR 65545 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-21

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Agate, Colorado post office has been filed. It... received a petition for review of the Postal Service's determination to close the Agate post office...

  9. 77 FR 1754 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-11

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the St. Anthony, Iowa post office has been filed. It... determination to close the St. Anthony post office in St. Anthony, Iowa. The petition for review was filed...

  10. 76 FR 71084 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-16

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Orchard, Iowa post office has been filed. It... received two petitions for review of the Postal Service's determination to close the Orchard post office...

  11. 76 FR 47614 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-08-05

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Pilot Grove, Iowa post office has been filed. It... of the Postal Service's determination to close the post office in Pilot Grove, Iowa. The...

  12. 76 FR 28103 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-05-13

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Gywnedd, Pennsylvania post office has been filed... of the Gwynedd, Pennsylvania post office. The petition, which was filed by Christina...

  13. 37 CFR 2.81 - Post publication.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 37 Patents, Trademarks, and Copyrights 1 2013-07-01 2013-07-01 false Post publication. 2.81 Section 2.81 Patents, Trademarks, and Copyrights UNITED STATES PATENT AND TRADEMARK OFFICE, DEPARTMENT OF COMMERCE RULES OF PRACTICE IN TRADEMARK CASES Publication and Post Publication § 2.81 Post publication....

  14. 76 FR 67498 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-01

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Venice, California post office has been filed. It... close the Venice post office in Venice, California. The petition for review was filed online on...

  15. 77 FR 4380 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-27

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Ponce de Leon, Missouri post office has been filed... de Leon Post Office in Ponce de Leon, Missouri. The petition for review received January 6, 2012,...

  16. 76 FR 75918 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-05

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Lanagan, Missouri post office has been filed. It... received a petition for review of the Postal Service's determination to close the Lanagan post office...

  17. 76 FR 70174 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-10

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Amoret, Missouri post office has been filed. It... received a petition for review of the Postal Service's determination to close the Amoret post office...

  18. 37 CFR 2.81 - Post publication.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 37 Patents, Trademarks, and Copyrights 1 2010-07-01 2010-07-01 false Post publication. 2.81 Section 2.81 Patents, Trademarks, and Copyrights UNITED STATES PATENT AND TRADEMARK OFFICE, DEPARTMENT OF COMMERCE RULES OF PRACTICE IN TRADEMARK CASES Publication and Post Publication § 2.81 Post publication....

  19. 76 FR 60946 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-30

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the North Canton, Connecticut post office has been... petition for review of the Postal Service's determination to close the North Canton post office in...

  20. 48 CFR 752.7029 - Post privileges.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 48 Federal Acquisition Regulations System 5 2013-10-01 2013-10-01 false Post privileges. 752.7029... FORMS SOLICITATION PROVISIONS AND CONTRACT CLAUSES Texts of USAID Contract Clauses 752.7029 Post privileges. For use in all USAID non-commercial contracts involving performance overseas. Post...

  1. 48 CFR 752.7029 - Post privileges.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 48 Federal Acquisition Regulations System 5 2012-10-01 2012-10-01 false Post privileges. 752.7029... FORMS SOLICITATION PROVISIONS AND CONTRACT CLAUSES Texts of USAID Contract Clauses 752.7029 Post privileges. For use in all USAID non-commercial contracts involving performance overseas. Post...

  2. 77 FR 5064 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-02-01

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Imperial, Texas post office has been filed. It... post office in Imperial, Texas. The first petition for review received January 11, 2012, was filed...

  3. 39 CFR 241.1 - Post offices.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 39 Postal Service 1 2011-07-01 2011-07-01 false Post offices. 241.1 Section 241.1 Postal Service... DISCONTINUANCE § 241.1 Post offices. (a) Establishment. See § 113.1 of this chapter. (b) Classification. As of July 1 each year, post offices are classified by the Postmaster General based on the allowable...

  4. 77 FR 1752 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-11

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Ashton, Iowa, post office has been filed. It... determination to close the Ashton post office in Ashton, Iowa. The first petition for review received December...

  5. 76 FR 55951 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-09

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Bentonville, Ohio post office has been filed. It... for review of the Postal Service's determination to close the Bentonville post office in...

  6. 76 FR 71083 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-16

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Andover, Illinois post office has been filed. It... received a petition for review of the Postal Service's determination to close the Andover post office...

  7. 48 CFR 752.7029 - Post privileges.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 48 Federal Acquisition Regulations System 5 2014-10-01 2014-10-01 false Post privileges. 752.7029... FORMS SOLICITATION PROVISIONS AND CONTRACT CLAUSES Texts of USAID Contract Clauses 752.7029 Post privileges. For use in all USAID non-commercial contracts involving performance overseas. Post...

  8. 76 FR 55952 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-09

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Velpen, Indiana post office has been filed. It... for review of the Postal Service's determination to close the Velpen post office in Velpen,...

  9. 76 FR 75569 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-02

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Prescott, Iowa post office has been filed. It... for review of the Postal Service's determination to close the Prescott post office in Prescott,...

  10. 48 CFR 752.7029 - Post privileges.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 48 Federal Acquisition Regulations System 5 2011-10-01 2011-10-01 false Post privileges. 752.7029... FORMS SOLICITATION PROVISIONS AND CONTRACT CLAUSES Texts of USAID Contract Clauses 752.7029 Post privileges. For use in all USAID non-commercial contracts involving performance overseas. Post...

  11. 77 FR 1751 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-11

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Strandquist, Minnesota post office has been filed... Postal Service's determination to close the Strandquist post office in Strandquist, Minnesota....

  12. 76 FR 75916 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-05

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Prince, West Virginia post office has been filed... received a petition for review of the Postal Service's determination to close the Prince post office...

  13. 76 FR 19149 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-04-06

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Wesleyville Post Office in Wesleyville... for review of the Postal Service's determination to close the Wesleyville, Pennsylvania post...

  14. 76 FR 75568 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-02

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the New Cambria, Kansas post office has been filed. It... received a petition for review of the Postal Service's determination to close the New Cambria post...

  15. 48 CFR 752.7029 - Post privileges.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 5 2010-10-01 2010-10-01 false Post privileges. 752.7029... FORMS SOLICITATION PROVISIONS AND CONTRACT CLAUSES Texts of USAID Contract Clauses 752.7029 Post privileges. For use in all USAID non-commercial contracts involving performance overseas. Post...

  16. 76 FR 44054 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-07-22

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Ukiah, California Main Post Office has been filed... review of the closing of the Ukiah Main Post Office, Ukiah, California. The petition, which was filed...

  17. 77 FR 1755 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-11

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Halsey, Nebraska post office has been filed. It... Halsey post office in Halsey, Nebraska. The first petition for review received December 16, 2011,...

  18. 76 FR 67001 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-28

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Witter, Arkansas post office has been filed. It... received a petition for review of the Postal Service's determination to close the Witter post office...

  19. 76 FR 51067 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-08-17

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Stoy, Illinois post office has been filed. It... Postal Service's determination to close the post office in Stoy, Illinois. The petition was filed by...

  20. 76 FR 61758 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-05

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Argyle, Florida post office has been filed. It... Postal Service's determination to close the Argyle post office in Argyle, Florida. The petition was...

  1. 76 FR 67003 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-28

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Adona, Arkansas post office has been filed. It... received a petition for review of the Postal Service's determination to close the Adona post office...

  2. 76 FR 60945 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-30

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Belk, Alabama post office has been filed. It... Postal Service's determination to close the Belk post office in Belk, Alabama. The petition was filed...

  3. 76 FR 58847 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-22

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Langston, Alabama post office has been filed. It... Postal Service's determination to close the Langston post office in Langston, Alabama. The petition...

  4. 77 FR 3809 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-25

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Pierceville, Indiana post office has been filed... Pierceville post office in Pierceville, Indiana. The first petition for review received December 28, 2011,...

  5. 76 FR 82003 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-29

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Fostoria, Iowa post office has been filed. It... post office in Fostoria, IA. The first petition for review received November 30, 2011, was filed...

  6. 76 FR 70173 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-10

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the West Edmeston, New York post office has been filed... received a petition for review of the Postal Service's determination to close the West Edmeston post...

  7. 37 CFR 2.81 - Post publication.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 37 Patents, Trademarks, and Copyrights 1 2012-07-01 2012-07-01 false Post publication. 2.81 Section 2.81 Patents, Trademarks, and Copyrights UNITED STATES PATENT AND TRADEMARK OFFICE, DEPARTMENT OF COMMERCE RULES OF PRACTICE IN TRADEMARK CASES Publication and Post Publication § 2.81 Post publication....

  8. 76 FR 62096 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-06

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: Notice is hereby... review of the Postal Service's determination to close the Redmon post office in Redmon, Illinois. The... Postal Service's determination to close the Redmon post office in Redmon, Illinois. The petition...

  9. 77 FR 4379 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-27

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Highfalls, North Carolina post office has been... Highfalls post office in Highfalls, North Carolina. The petition for review received January 11, 2012,...

  10. 76 FR 70175 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-10

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the New Boston, Illinois post office has been filed... received two petitions for review of the Postal Service's determination to close the New Boston post...

  11. 37 CFR 2.81 - Post publication.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 37 Patents, Trademarks, and Copyrights 1 2011-07-01 2011-07-01 false Post publication. 2.81 Section 2.81 Patents, Trademarks, and Copyrights UNITED STATES PATENT AND TRADEMARK OFFICE, DEPARTMENT OF COMMERCE RULES OF PRACTICE IN TRADEMARK CASES Publication and Post Publication § 2.81 Post publication....

  12. 37 CFR 2.81 - Post publication.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 37 Patents, Trademarks, and Copyrights 1 2014-07-01 2014-07-01 false Post publication. 2.81 Section 2.81 Patents, Trademarks, and Copyrights UNITED STATES PATENT AND TRADEMARK OFFICE, DEPARTMENT OF COMMERCE RULES OF PRACTICE IN TRADEMARK CASES Publication and Post Publication § 2.81 Post publication....

  13. 76 FR 61760 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-05

    ... [Docket No. A2011-88; Order No. 880 Post Office Closing AGENCY: Postal Regulatory Commission. ACTION... post office has been filed. It identifies preliminary steps and provides a procedural schedule... received a petition for review of the Postal Service's determination to close the Breaks post office...

  14. 76 FR 28104 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-05-13

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Tateville, Kentucky post office has been filed. It... closing of the Tateville, Kentucky post office. Petitions were filed by Rebecca Kroell, Glenn Walker,...

  15. 39 CFR 241.1 - Post offices.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 39 Postal Service 1 2010-07-01 2010-07-01 false Post offices. 241.1 Section 241.1 Postal Service... DISCONTINUANCE § 241.1 Post offices. (a) Establishment. See § 113.1 of this chapter. (b) Classification. As of July 1 each year, post offices are classified by the Postmaster General based on the allowable...

  16. 76 FR 45301 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-07-28

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Unionville, Iowa post office has been filed. It... closing of the post office in Unionville, Iowa. The petition, which was filed by Dorothy Jean...

  17. 76 FR 51066 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-08-17

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Rex, North Carolina post office has been filed. It... Postal Service's determination to close the post office in Rex, North Carolina. The petition was filed...

  18. Statins for post resuscitation syndrome.

    PubMed

    Kämäräinen, Antti; Virkkunen, Ilkka; Silfvast, Tom; Tenhunen, Jyrki

    2009-07-01

    After sudden cardiac arrest, successful resuscitation and return of spontaneous circulation, a multi-faceted ischaemia/reperfusion related disorder develops. This condition now known as post resuscitation syndrome is characterised by marked increases in the inflammatory response and changes in coagulation profile and vascular reactivity. Additionally, the production of reactive oxygen species and activation of cytotoxic cascades of metabolism add to these injury mechanisms resulting in multiorgan perfusion deficits and dysfunction. Especially in the cerebrum these injuries may be the cause of significant morbidity and mortality. Recent evidence has shown that statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) exert numerous beneficial effects in cardiovascular diseases irrespective of the lipid status. Remarkably, these pleiotropic effects seem to extended beyond cardiovascular diseases such as immunomodulative and antioxidative properties. We hypothesised that administration of statins early in the post resuscitation phase would prove beneficial in the resuscitated patient via several pleiotropic effects. These include inhibition of excessive coagulation and inflammatory response, suppression of oxygen radical production and improved vascular reactivity. The discussed effects are mediated via multiple pathways activated in the cardiac arrest victim, to which statins have been shown to have a beneficial modulating effect in experimental settings and non-cardiac arrest patients. To test this hypothesis in clinical practice, a randomized, controlled trial with sufficient power and standardised post resuscitation treatment would be necessary. The generally good tolerance of statin therapy with minimal adverse effects would support this experiment, although a parenteral form of the drug to ensure adequate dosage might be a prerequisite. PMID:19254829

  19. Hyperbaric post weld heat treatment

    SciTech Connect

    Saunderson, S.; Waller, D.

    1983-05-01

    This paper describes a sub-sea hyperbaric Post Weld Heat Treatment (PWHT) system developed jointly by SHELL UK EXPLORATION and PRODUCTION and COMEX DIVING. It discusses: assessment of power requirements and equipment, initial tests conducted in the COMEX hydrosphere and in shallow water in Marseille, and full scale North Sea trials at - 150 m, comparing the performance and results of two separate power sources and control units. Particular attention is drawn to the importance of the elements, insulation and controls used to achieve uniform distribution of heat at the required temperature in a HELIOX environment.

  20. STS-109 Post Flight Presentation

    NASA Astrophysics Data System (ADS)

    2002-04-01

    The STS-109 Post Flight presentation begins with Mission Specialists Nancy J. Currie, Michael J. Massimino, James H. Newman, and Richard M. Linnehan shown getting suited on launch day. Actual footage of the liftoff of the Space Shuttle Columbia is shown. Five spacewalks are performed to service the Hubble Space Telescope. Richard Linnehan and John Grunsfield are replacing solar arrays, connectors and power control units on the Hubble Space Telescope. Mission Specialist Nancy Currie will use Space Shuttle Columbia's robotic arm to grab the telescope, move it away from the orbiter and release it. A look at the coast of South America is also presented.

  1. Delayed Post-Traumatic Anisocoria.

    PubMed

    Ergül, Dursun Fırat; Ekemen, Serdar; Özdemir, Özcan; Uzan, Çağdaş; Yelken, Birgül

    2015-06-01

    Post-traumatic carotid artery dissection is one of the major causes of ischemic stroke in young patients; its diagnosis remains a challenge for clinicians because of its variable clinical presentation. An otherwise healthy 37-year-old man was referred to the intensive care unit of our faculty for the management of multiple trauma because of a car accident. At 11 days from admission, his doctor noticed the advent of anisocoria. A prompt treatment was instituted with anti-platelet and-coagulant agents. The patient had a complete resolution of symptoms. The prognosis was good, and the patient achieved a complete clinical recovery. He was discharged without any sequelae. PMID:27366498

  2. [Post-traumatic stress disorder].

    PubMed

    Ponteva, Matti; Henriksson, Markus; Isoaho, Raimo; Laukkala, Tanja; Männikkö, Timo; Punamäki, Raija-Leena; Wahlbeck, Kristian

    2009-01-01

    Psychosocial support and careful monitoring are recommended for acute stress reaction (ASR) and acute stress disorder (ASD). If symptoms require, short focused cognitive-behavioural psychotherapy can be used for ASD. Medication is rarely necessary, but sleeping pills can be used for a short period. Trauma-focused psychotherapeutic interventions are first-line treatment for post-traumatic stress disorder. SSRI or SNRI antidepressant medication is also effective. There is less evidence on antipsychotic and antiepileptic medication. Psychotherapeutic interventions and medication can be, and often are, combined. Children, the elderly, and military and peacekeeping personnel need interventions that are tailored to their needs. PMID:19839195

  3. Post-Traumatic Visual Loss

    PubMed Central

    Atkins, Edward J.; Newman, Nancy J.; Biousse, Valérie

    2010-01-01

    Visual loss following head trauma is common, and the diagnosis can be challenging for the neurologist called to perform an emergency room assessment. The approach to the patient with post-traumatic visual loss is complicated by a wide range of potential ocular and brain injuries with varying pathophysiology. In addition to direct injuries of the eye and orbit, traumatic optic neuropathies, carotid cavernous fistulas, and damage to the intracranial visual pathways are classic causes of visual loss after head trauma. This review provides an update on the diagnosis and management of these conditions. PMID:18660739

  4. In vitro evaluation of glass fiber post

    PubMed Central

    Sharma, Navneet; Singh, Harpal

    2012-01-01

    Statement of problem: Techniques and recommendations for the restoration of endodontically treated teeth have changed from the use of custom cast metal post and core system to glass fiber-reinforced (GFRC) post and composite core system. Has this latest prefabricated glass fiber reinforced post and composite core system increased the fracture resistance of teeth and reduced the incidence of unrestorable root fractures. Purpose: The purpose of this study was to evaluate the incidence of root fracture and mode of failure of endodontically treated teeth restored with two different post and core systems. Material and Methods: Forty maxillary central incisors were randomly divided into two groups. (n=20). All teeth received endodontic treatment. First group was restored with custom cast post and core system. Second group was restored with glass fiber post and composite core system. In Both the groups posts were cemented with adhesive resin cement. Compressive load was applied at an angle of 130 to the long axis of teeth at a cross head speed of 1 mm/min until fracture occurred. Data were analyzed with student “t” test P<.001. Results: The mean value for fracture resistance was (331.4025) N in Group -I Custom cast Ni-Cr post and core and (237.0625) N in Group -II Glass fiber reinforced post and composite core system. Students “t” test shows the significant difference in fracture resistance of two groups. Conclusion: This study showed that the incidence of root fracture was significantly higher in custom cast Ni-Cr post and core system than glass fiber post and composite core system. A more favourable mode of failure was observed in teeth restored with Group II glass fiber post system. Key words:Post-and-core technique, glass fiber post, cast post and-core system, fracture resistance, endodontically treated teeth. PMID:24558556

  5. Post-Secularism, Religious Knowledge and Religious Education

    ERIC Educational Resources Information Center

    Carr, David

    2012-01-01

    Post-secularism seems to follow in the wake of other (what are here called) "postal" perspectives--post-structuralism, postmodernism, post-empiricism, post-positivism, post-analytical philosophy, post-foundationalism and so on--in questioning or repudiating what it takes to be the epistemic assumptions of "modernism." To be sure, post-secularism…

  6. An SEM Approach for the Evaluation of Intervention Effects Using Pre-Post-Post Designs

    ERIC Educational Resources Information Center

    Mun, Eun Young; von Eye, Alexander; White, Helene R.

    2009-01-01

    This study analyzes latent change scores using latent curve models (LCMs) for evaluation research with pre-post-post designs. The article extends a recent article by Willoughby, Vandergrift, Blair, and Granger (2007) on the use of LCMs for studies with pre-post-post designs, and demonstrates that intervention effects can be better tested using…

  7. 14 CFR 417.415 - Post-launch and post-flight-attempt hazard controls.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 14 Aeronautics and Space 4 2013-01-01 2013-01-01 false Post-launch and post-flight-attempt hazard controls. 417.415 Section 417.415 Aeronautics and Space COMMERCIAL SPACE TRANSPORTATION, FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION LICENSING LAUNCH SAFETY Ground Safety § 417.415 Post-launch and post-flight-attempt hazard...

  8. [Post-Lyme disease syndrome].

    PubMed

    Błaut-Jurkowska, Justyna; Jurkowski, Marcin

    2016-02-01

    Lyme disease is a chronic infectious disease caused by the bacteria, spirochete of the Borrelia type. Skin, nervous system, musculoskeletal system and heart may be involved in the course of the disease. The prognosis for properly treated Lyme disease is usually good. However, in about 5% of patients so called Post-Lyme disease syndrome (PLSD) develops. It is defined as a syndrome of subjective symptoms persisting despite proper treatment of Borrelia burgdorferi infection. The most common symptoms include: fatigue, muscle and joint pain, and problems with memory and concentration. Pathogenesis of PLDS remains unknown. The differential diagnosis should include neurological, rheumatic and mental diseases. Till now there is no causative treatment of PLDS. In relieving symptom rehabilitation, painkillers, anti-inflammatory and antidepressants medicines are recommended. Emotional and psychological supports are also necessary. Non-specific symptoms reported by patients with post- Lyme disease syndrome raise the suspicion of other pathologies. This can lead to misdiagnosis and implementation of unnecessary, potentially harmful to the patient's therapy. An increase in tick-borne diseases needs to increase physicians awareness of these issues. PMID:27000820

  9. Sterile post-traumatic immunosuppression.

    PubMed

    Islam, Md Nahidul; Bradley, Benjamin A; Ceredig, Rhodri

    2016-04-01

    After major trauma, the human immune system initiates a series of inflammatory events at the injury site that is later followed by suppression of local inflammation favoring the repair and remodeling of the damaged tissues. This local immune response involves complex interactions between resident cells such as macrophages and dendritic cells, soluble mediators such as cytokines and chemokines, and recruited cells such as neutrophils, monocytes and mesenchymal stromal cells. If of sufficient magnitude, these initial immune responses nevertheless have systemic consequences resulting in a state called post-traumatic immunosuppression (PTI). However, controversy exists regarding the exact immunological changes occurring in systemic compartments triggered by these local immune responses. PTI is one of the leading causes of post-surgical mortality and makes patients vulnerable to hospital-acquired infections, multiple organ failure and many other complications. In addition, hemorrhage, blood transfusion, immunesenescence and immunosuppressant drugs aggravate PTI. PTI has been intensively studied, but published results are frequently cloudy. The purpose of this review is to focus on the contributions made by different responsive modalities to immunosuppression following sterile trauma and to try to integrate these into an overall scheme of PTI. PMID:27195120

  10. Sterile post-traumatic immunosuppression

    PubMed Central

    Islam, Md Nahidul; Bradley, Benjamin A; Ceredig, Rhodri

    2016-01-01

    After major trauma, the human immune system initiates a series of inflammatory events at the injury site that is later followed by suppression of local inflammation favoring the repair and remodeling of the damaged tissues. This local immune response involves complex interactions between resident cells such as macrophages and dendritic cells, soluble mediators such as cytokines and chemokines, and recruited cells such as neutrophils, monocytes and mesenchymal stromal cells. If of sufficient magnitude, these initial immune responses nevertheless have systemic consequences resulting in a state called post-traumatic immunosuppression (PTI). However, controversy exists regarding the exact immunological changes occurring in systemic compartments triggered by these local immune responses. PTI is one of the leading causes of post-surgical mortality and makes patients vulnerable to hospital-acquired infections, multiple organ failure and many other complications. In addition, hemorrhage, blood transfusion, immunesenescence and immunosuppressant drugs aggravate PTI. PTI has been intensively studied, but published results are frequently cloudy. The purpose of this review is to focus on the contributions made by different responsive modalities to immunosuppression following sterile trauma and to try to integrate these into an overall scheme of PTI. PMID:27195120

  11. Post-Gastric Bypass Hypoglycemia.

    PubMed

    Rariy, Chevon M; Rometo, David; Korytkowski, Mary

    2016-02-01

    Obesity is a major public health problem worldwide. Obesity-related illnesses, such as coronary heart disease, type 2 diabetes, hypertension, dyslipidemia, stroke, sleep apnea, and several forms of cancer (endometrial, breast, and colon), contribute to a significant number of deaths in the USA. Bariatric surgery, including the Roux-en-Y gastric bypass (RYGB) procedure, has demonstrated significant improvements in obesity and obesity-related co-morbidities and is becoming more popular as the number of obese individuals rises. Despite the reported benefits of bariatric surgery, there are potential complications that physicians need to be aware of as the number of patients undergoing these procedures continues to increase. One challenging and potentially life-threatening complication that to date is not well understood is post-RYGB surgery hypoglycemia (PGBH). In this review, we will present the definition, historical perspective, diagnostic approach, currently available treatment options, and anecdotal assessment and treatment algorithm for this disorder. PMID:26868861

  12. Cerebral pathology post heart transplantation.

    PubMed

    Peteghem, S Van; Pauw, M De

    2015-04-01

    Cerebral pathology is frequently encountered post heart transplantation with a cumulative incidence of about 80% after 15 years. A broad spectrum of disease entities is reported, from minor abnormalities to life-threatening diseases. Although cerebral infections and malignancies are rare in this patient population, they have a high mortality rate. Since 1991, 171 orthotopic heart transplantations were performed at the Ghent University Hospital with a 10-year survival rate of 75%. Severe cerebral complications occurred in 10 patients, with epilepsy in 2 patients, cerebrovascular accidents in 4 patients, cerebral infections in 3 patients and a cerebral malignancy in 1 patient, resulting in a fatal outcome in 7 patients. We present four of these cases. PMID:25292206

  13. [Post-dural puncture headache].

    PubMed

    Radke, K; Radke, O C

    2013-02-01

    Headache following dural puncture is a typical complication of neuraxial analgesia and can impair the ability to perform activities of daily living up to incapacitation. The use of thin, atraumatic needles and special puncture techniques (e.g. reinsertion of the stylet) can prevent the majority of post-dural puncture headaches (PDPH). One of the most effective measures to prevent headache after accidental dural puncture is the intrathecal or epidural administration of morphine. When the diagnosis of PDPH is confirmed after excluding relevant differential diagnoses, some of which are potentially life-threatening, caffeine, theophylline and non-opioid analgesics are effective agents to reduce the severity of the symptoms. Traditional measures, such as strict bed rest and hyperhydration can no longer be recommended. If invasive treatment of the headache is warranted an epidural blood patch is still the method of choice with a high rate of success. PMID:23400710

  14. STS-67 post flight presentation

    NASA Astrophysics Data System (ADS)

    1995-04-01

    This video is the post-flight presentation by the astronauts of the STS-67 Space Shuttle Mission. The astronauts were: Steve Oswald (Mission Commander), Bill Gregory (Shuttle Pilot), John Grunsfeld (Mission Specialist), Sam Durrance (Payload Specialist), Ron Parise (Payload Specialist), and Tammy Jernigan (Payload Commander). Footage includes: pre-launch suitup and launch (liftoff), the deployment of the telescope package payload (Hopkins UV telescope, Wisconsin UV polarimeter, and Astrostar Tracker) for their astronomical observations of different stellar objects, inside Shuttle shots of data collection stations, protein crystal growth experiments, medical BSO of head and eye functions in microgravity environment, storm activity over the United States and other Earth observation shots, Mid-deck Act Control Experiments, school-Shuttle direct radio communication, and descent and landing footage. This launch was a night launch and the flight was a 17 day flight (extended two days from original flight plan).

  15. Post-ischemic diastolic dysfunction.

    PubMed

    Marsch, S C; Dalmas, S; Philbin, D M; Wanigasekera, V A; Ryder, W A; Wong, L S; Foëx, P

    1994-12-01

    Though a sustained post-ischemic decrease in contractile function has been clearly established, post-ischemic diastolic function has not been thoroughly investigated. Accordingly, 11 anesthetized (isoflurane 1%) open-chest beagles were instrumented to measure left ventricular pressure and dimensions (circumferential length and wall thickness) in an apicoanterior area supplied by the left anterior descending coronary artery (LAD). Pressure-dimension relations were modified by stepwise infusion and withdrawal of 200 mL of the animals' own blood during baseline, 45 minutes partial occlusion of the LAD (systolic bulging), and 60 minutes after the onset of reperfusion. Stiffness constants were derived from the end-diastolic pressure-length and stress-strain relations, respectively. Myocardial ischemia was associated with significant (P < 0.05) alterations of the following parameters of diastolic function: (1) 47% increase in end-diastolic pressure; (2) 22% decrease in peak negative dP/dt; (3) 9% increase in the time constant of isovolumic relaxation (tau); (4) postcystolic contraction; (5) 6% increase in end-diastolic length and 10% decrease in end-diastolic thickness; (6) 12% increase in unstressed length (creep) and 13% decrease in unstressed thickness; (7) 51% increase in chamber stiffness and a 63% increase in myocardial stiffness; and (8) 40% decrease in the peak lengthening rate. After 60 minutes of reperfusion, only end-diastolic pressure and tau had returned to baseline values whereas systolic shortening fraction, postsystolic contraction, and end-diastolic and unstressed dimensions had only partially recovered. No recovery occurred in peak negative dP/dt, chamber stiffness, myocardial stiffness, and peak lengthening rate. Thus, both myocardial ischemia and reperfusion are associated with complex changes in global and regional left ventricular diastolic function. PMID:7880987

  16. Discovery of the macrocycle 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene (SB1518), a potent Janus kinase 2/fms-like tyrosine kinase-3 (JAK2/FLT3) inhibitor for the treatment of myelofibrosis and lymphoma.

    PubMed

    William, Anthony D; Lee, Angeline C-H; Blanchard, Stéphanie; Poulsen, Anders; Teo, Ee Ling; Nagaraj, Harish; Tan, Evelyn; Chen, Dizhong; Williams, Meredith; Sun, Eric T; Goh, Kee Chuan; Ong, Wai Chung; Goh, Siok Kun; Hart, Stefan; Jayaraman, Ramesh; Pasha, Mohammed Khalid; Ethirajulu, Kantharaj; Wood, Jeanette M; Dymock, Brian W

    2011-07-14

    Discovery of the activating mutation V617F in Janus Kinase 2 (JAK2(V617F)), a tyrosine kinase critically involved in receptor signaling, recently ignited interest in JAK2 inhibitor therapy as a treatment for myelofibrosis (MF). Herein, we describe the design and synthesis of a series of small molecule 4-aryl-2-aminopyrimidine macrocycles and their biological evaluation against the JAK family of kinase enzymes and FLT3. The most promising leads were assessed for their in vitro ADME properties culminating in the discovery of 21c, a potent JAK2 (IC(50) = 23 and 19 nM for JAK2(WT) and JAK2(V617F), respectively) and FLT3 (IC(50) = 22 nM) inhibitor with selectivity against JAK1 and JAK3 (IC(50) = 1280 and 520 nM, respectively). Further profiling of 21c in preclinical species and mouse xenograft and allograft models is described. Compound 21c (SB1518) was selected as a development candidate and progressed into clinical trials where it is currently in phase 2 for MF and lymphoma. PMID:21604762

  17. 6. Photocopy of a 1944 architectural drawing titled: Post Office ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    6. Photocopy of a 1944 architectural drawing titled: Post Office & Post Exchange. Elevations, Sections and Details. 1-29-44 - Madigan Hospital, Post Office & Post Exchange, Bounded by Wilson & McKinley Avenues & Garfield & Lincoln Streets, Tacoma, Pierce County, WA

  18. 46 CFR 196.12-1 - Posting.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 46 Shipping 7 2013-10-01 2013-10-01 false Posting. 196.12-1 Section 196.12-1 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) OCEANOGRAPHIC RESEARCH VESSELS OPERATIONS Stability Letter § 196.12-1 Posting. If a stability letter is issued in accordance with the requirements in § 170.120 of this chapter, it must be posted...

  19. 46 CFR 97.11-1 - Posting.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 46 Shipping 4 2011-10-01 2011-10-01 false Posting. 97.11-1 Section 97.11-1 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) CARGO AND MISCELLANEOUS VESSELS OPERATIONS Stability Letter § 97.11-1 Posting. If a stability letter is issued under § 170.120 of this chapter, it must be posted under glass or other suitable...

  20. Nurses management of post-operative pain.

    PubMed

    Buckley, H

    2000-06-01

    Nurses have the responsibility of adequately managing patients' post-operative pain. This literature review assesses whether nurses' management of post-operative pain is adequate or not, according to the literature findings. The findings reveal that nurses' management of patients' post-operative pain is not adequate and implies the concurrent need for improved nurse education and practice. The findings also indicate a need for ongoing research of this phenomenon. PMID:11855003

  1. [Post-traumatic stress disorder after childbirth].

    PubMed

    Korábová, I; Masopustová, Z

    2016-01-01

    The aim of this paper is to introduce the issue of post-traumatic stress disorder after childbirth to health care professionals. The text focuses on the diagnostic definition of post-traumatic stress disorder after childbirth, symptoms, physiological background, prevalence, course, risk factors and consequences of post-traumatic stress disorder after childbirth for a woman, her child and her partner. Options for interventions and therapy are outlined as well. PMID:26982058

  2. MRO DKF Post-Processing Tool

    NASA Technical Reports Server (NTRS)

    Ayap, Shanti; Fisher, Forest; Gladden, Roy; Khanampompan, Teerapat

    2008-01-01

    This software tool saves time and reduces risk by automating two labor-intensive and error-prone post-processing steps required for every DKF [DSN (Deep Space Network) Keyword File] that MRO (Mars Reconnaissance Orbiter) produces, and is being extended to post-process the corresponding TSOE (Text Sequence Of Events) as well. The need for this post-processing step stems from limitations in the seq-gen modeling resulting in incorrect DKF generation that is then cleaned up in post-processing.

  3. STS 63: Post flight presentation

    NASA Astrophysics Data System (ADS)

    1995-02-01

    At a post flight conference, Captain Jim Wetherbee, of STS Flight 63, introduces each of the other members of the STS 63 crew (Eileen Collins, Pilot; Dr. Bernard Harris, Payload Commander; Dr. Michael Foale, Mission Specialist from England; Dr. Janice Voss, Mission Specialist; and Colonel Vladimir Titor, Mission Specialist from Russia), gave a short autobiography of each member and a brief description of their assignment during this mission. A film was shown that included the preflight suit-up, a view of the launch site, the actual night launch, a tour of the Space Shuttle and several of the experiment areas, several views of earth and the MIR Space Station and cosmonauts, the MlR-Space Shuttle rendezvous, the deployment of the Spartan Ultraviolet Telescope, Foale and Harris's EVA and space walk, the retrieval of Spartan, and the night entry home, including the landing. Several spaceborne experiments were introduced: the radiation monitoring experiment, environment monitoring experiment, solid surface combustion experiment, and protein crystal growth and plant growth experiments. This conference ended with still, color pictures, taken by the astronauts during the entire STS 63 flight, being shown.

  4. STS 63: Post Flight Presentation

    NASA Technical Reports Server (NTRS)

    1995-01-01

    At a post flight conference, Captain Jim Wetherbee, of STS Flight 63, introduces each of the other members of the STS 63 crew (Eileen Collins, Pilot; Dr. Bernard Harris, Payload Commander; Dr. Michael Foale, Mission Specialist from England; Dr. Janice Voss, Misssion Specialist; and Colonel Vladimir Titor, Misssion Specialist from Russia. A short biography of each member and a brief description of their assignment during this mission is given. A film was shown that included the preflight suit-up, a view of the launch site, the actual night launch, a tour of the Space Shuttle and several of the experiment areas, several views of earth and the MIR Space Station and cosmonauts, the MIR-Space Shuttle rendezvous, the deployment of the Spartan Ultraviolet Telescope, Foale and Harris's EVA and space walk, the retrieval of Spartan, and the night entry home, including the landing. Several spaceborne experiments were introduced: the radiation monitoring experiment, environment monitoring experiment, solid surface combustion experiment, and protein crystal growth and plant growth experiments. This conference ended with still, color pictures, taken by the astronauts during the entire STS 63 flight, being shown.

  5. Post partum pelvic floor changes.

    PubMed

    Fonti, Ylenia; Giordano, Rosalba; Cacciatore, Alessandra; Romano, Mattea; La Rosa, Beatrice

    2009-10-01

    Pelvic-perineal dysfunctions, are the most common diseases in women after pregnancy. Urinary incontinence and genital prolapsy, often associated, are the most important consequences of childbirth and are determined by specific alterations in the structure of neurological and musculo-fascial pelvic support.Causation is difficult to prove because symptom occur remote from delivery.Furthermore it is unclear whether changes are secondary to the method of childbirth or to the pregnancy itself.This controversy fuels the debate about whether or not women should be offered the choice of elective caesarean delivery to avoid the development of subsequent pelvic floor disfunction.But it has been demonstrated that pregnancy itself, by means of mechanical changes of pelvic statics and changes in hormones, can be a significant risk factor for these diseases. Especially is the first child to be decisive for the stability of the pelvic floor.During pregnancy, the progressive increase in volume of the uterus subject perineal structures to a major overload. During delivery, the parties present and passes through the urogenital hiatus leading to growing pressure on the tissues causing the stretching of the pelvic floor with possible muscle damage, connective tissue and / or nervous.In this article we aim to describe genitourinary post partum changes with particular attention to the impact of pregnancy or childbirth on these changes. PMID:22439048

  6. Carbohydrate post-glycosylational modifications

    PubMed Central

    Yu, Hai; Chen, Xi

    2008-01-01

    Carbohydrate modification is a common phenomenon in nature. Many carbohydrate modifications such as some epimerization, O-acetylation, O-sulfation, O-methylation, N-deacetylation, and N-sulfation, take place after the formation of oligosaccharide or polysaccharide backbones. These modifications can be categorized as carbohydrate post-glycosylational modifications (PGMs). Carbohydrate PGMs further extend the complexity of the structures and the synthesis of carbohydrates and glycoconjugates. They also increase the capacity of the biological information that can be controlled by finely tuning the structures of carbohydrates. Developing efficient methods to obtain structurally defined naturally occurring oligosaccharides, polysaccharides, and glycoconjugates with carbohydrate PGMs is essential for understanding the biological significance of carbohydrate PGMs. Combine with high-throughput screening methods, synthetic carbohydrates with PGMs are invaluable probes in structure-activity relationship studies. We illustrate here several classes of carbohydrates with PGMs and their applications. Recent progress in chemical, enzymatic, and chemoenzymatic syntheses of these carbohydrates and their derivatives are also presented. PMID:17340000

  7. STS-113 Post Flight Presentation

    NASA Astrophysics Data System (ADS)

    2002-01-01

    The STS-113 post-flight presentation begins with a view of Mission Specialists Michael E. Lopez-Alegria and John B. Herrington getting suited for the space mission. The STS-113 crew consists of: Commander James D. Wetherbee, Pilot Paul Lockhart, Mission Specialists Michael Lopez-Alegria and John Herrington. Cosmonauts Valery Korzun, and Sergei Treschev, and astronaut Peggy Whitson who are all members of the expedition five crew, and Commander Kenneth Bowersox, Flight Engineers Nikolai Budarin and Donald Pettit, members of Expedition Six. The main goal of this mission is to take Expedition Six up to the International Space Station and Return Expedition Five to the Earth. The second objective is to install the P(1) Truss segment. Three hours prior to launch, the crew of Expedition Six along with James Wetherbee, Paul Lockhart, Michael Lopez-Alegria and John Herrington are shown walking to an astrovan, which takes them to the launch pad. The actual liftoff is presented. Three Extravehicular Activities (EVA)'s are performed on this mission. Michael Lopez-Alegria and John Herrington are shown performing EVA 1 and EVA 2 which include making connections between the P1 and S(0) Truss segments, and installing fluid jumpers. A panoramic view of the ISS with the Earth in the background is shown. The grand ceremony of the crew exchange is presented. The astronauts performing everyday duties such as brushing teeth, washing hair, sleeping, and eating pistachio nuts are shown. The actual landing of the Space Shuttle is presented.

  8. Post-transplant lymphoproliferative disorders.

    PubMed

    Dharnidharka, Vikas R; Webster, Angela C; Martinez, Olivia M; Preiksaitis, Jutta K; Leblond, Veronique; Choquet, Sylvain

    2016-01-01

    Post-transplant lymphoproliferative disorders (PTLDs) are a group of conditions that involve uncontrolled proliferation of lymphoid cells as a consequence of extrinsic immunosuppression after organ or haematopoietic stem cell transplant. PTLDs show some similarities to classic lymphomas in the non-immunosuppressed general population. The oncogenic Epstein-Barr virus (EBV) is a key pathogenic driver in many early-onset cases, through multiple mechanisms. The incidence of PTLD varies with the type of transplant; a clear distinction should therefore be made between the conditions after solid organ transplant and after haematopoietic stem cell transplant. Recipient EBV seronegativity and the intensity of immunosuppression are among key risk factors. Symptoms and signs depend on the localization of the lymphoid masses. Diagnosis requires histopathology, although imaging techniques can provide additional supportive evidence. Pre-emptive intervention based on monitoring EBV levels in blood has emerged as the preferred strategy for PTLD prevention. Treatment of established disease includes reduction of immunosuppression and/or administration of rituximab (a B cell-specific antibody against CD20), chemotherapy and EBV-specific cytotoxic T cells. Despite these strategies, the mortality and morbidity remains considerable. Patient outcome is influenced by the severity of presentation, treatment-related complications and risk of allograft loss. New innovative treatment options hold promise for changing the outlook in the future. PMID:27189056

  9. 49 CFR 238.211 - Collision posts.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... body structure. (3) Prior to or during structural deformation, each collision post acting together with... structural protection described in paragraph (a) of this section, either: (1) Two forward collision posts... structural protection described in paragraphs (a) and (b) of this section, two forward collision...

  10. 49 CFR 238.211 - Collision posts.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... body structure. (3) Prior to or during structural deformation, each collision post acting together with... structural protection described in paragraph (a) of this section, either: (1) Two forward collision posts... structural protection described in paragraphs (a) and (b) of this section, two forward collision...

  11. 49 CFR 238.211 - Collision posts.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... body structure. (3) Prior to or during structural deformation, each collision post acting together with... structural protection described in paragraph (a) of this section, either: (1) Two forward collision posts... structural protection described in paragraphs (a) and (b) of this section, two forward collision...

  12. 49 CFR 238.211 - Collision posts.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... body structure. (3) Prior to or during structural deformation, each collision post acting together with... structural protection described in paragraph (a) of this section, either: (1) Two forward collision posts... structural protection described in paragraphs (a) and (b) of this section, two forward collision...

  13. 49 CFR 238.211 - Collision posts.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... body structure. (3) Prior to or during structural deformation, each collision post acting together with... structural protection described in paragraph (a) of this section, either: (1) Two forward collision posts... structural protection described in paragraphs (a) and (b) of this section, two forward collision...

  14. 77 FR 3807 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-25

    ... informs the public that an appeal of the closing of the Badger, Iowa post office has been filed. It... Commission received four petitions for review of the Postal Service's determination to close the Badger post office in Badger, Iowa. The first petition for review received December 30, 2011, was filed by Myron...

  15. 76 FR 71085 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-16

    ... informs the public that an appeal of the closing of the Deer Grove, Illinois post office has been filed... received a petition for review of the Postal Service's determination to close the Deer Grove post office in Deer Grove, Illinois. The petition for review was filed by Galen R. Hooper (Petitioner) and...

  16. Constructing Relationships in Post-Divorce Therapy.

    ERIC Educational Resources Information Center

    Chenail, Ronald J.; And Others

    This paper introduces a post-divorce therapy project in which therapists focus on communication patterns and help families resolve their problematic post-divorce situations by co-creating more useful ways of dealing with their disputes and conflicts. The paper also examines how therapists attempt to construct alternative relationships with and…

  17. 46 CFR 97.11-1 - Posting.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ..., DEPARTMENT OF HOMELAND SECURITY (CONTINUED) CARGO AND MISCELLANEOUS VESSELS OPERATIONS Stability Letter § 97.11-1 Posting. If a stability letter is issued under § 170.120 of this chapter, it must be posted under glass or other suitable transparent material in the pilothouse of the vessel....

  18. 46 CFR 196.12-1 - Posting.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ..., DEPARTMENT OF HOMELAND SECURITY (CONTINUED) OCEANOGRAPHIC RESEARCH VESSELS OPERATIONS Stability Letter § 196.12-1 Posting. If a stability letter is issued in accordance with the requirements in § 170.120 of this chapter, it must be posted under glass or other suitable transparent material in the pilothouse...

  19. 46 CFR 97.11-1 - Posting.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ..., DEPARTMENT OF HOMELAND SECURITY (CONTINUED) CARGO AND MISCELLANEOUS VESSELS OPERATIONS Stability Letter § 97.11-1 Posting. If a stability letter is issued under § 170.120 of this chapter, it must be posted under glass or other suitable transparent material in the pilothouse of the vessel....

  20. 46 CFR 196.12-1 - Posting.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ..., DEPARTMENT OF HOMELAND SECURITY (CONTINUED) OCEANOGRAPHIC RESEARCH VESSELS OPERATIONS Stability Letter § 196.12-1 Posting. If a stability letter is issued in accordance with the requirements in § 170.120 of this chapter, it must be posted under glass or other suitable transparent material in the pilothouse...

  1. 46 CFR 196.12-1 - Posting.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ..., DEPARTMENT OF HOMELAND SECURITY (CONTINUED) OCEANOGRAPHIC RESEARCH VESSELS OPERATIONS Stability Letter § 196.12-1 Posting. If a stability letter is issued in accordance with the requirements in § 170.120 of this chapter, it must be posted under glass or other suitable transparent material in the pilothouse...

  2. 46 CFR 97.11-1 - Posting.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ..., DEPARTMENT OF HOMELAND SECURITY (CONTINUED) CARGO AND MISCELLANEOUS VESSELS OPERATIONS Stability Letter § 97.11-1 Posting. If a stability letter is issued under § 170.120 of this chapter, it must be posted under glass or other suitable transparent material in the pilothouse of the vessel....

  3. 46 CFR 196.12-1 - Posting.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ..., DEPARTMENT OF HOMELAND SECURITY (CONTINUED) OCEANOGRAPHIC RESEARCH VESSELS OPERATIONS Stability Letter § 196.12-1 Posting. If a stability letter is issued in accordance with the requirements in § 170.120 of this chapter, it must be posted under glass or other suitable transparent material in the pilothouse...

  4. 46 CFR 97.11-1 - Posting.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ..., DEPARTMENT OF HOMELAND SECURITY (CONTINUED) CARGO AND MISCELLANEOUS VESSELS OPERATIONS Stability Letter § 97.11-1 Posting. If a stability letter is issued under § 170.120 of this chapter, it must be posted under glass or other suitable transparent material in the pilothouse of the vessel....

  5. Post-bone marrow transplant thrombotic microangiopathy.

    PubMed

    Obut, F; Kasinath, V; Abdi, R

    2016-07-01

    Thrombotic microangiopathy (TMA) is a systemic disease characterized by microangiopathic hemolytic anemia, thrombocytopenia and organ failure. Post-bone marrow transplant TMA (post-BMT TMA) is a life-threatening condition that has been reported to afflict between 0.5 and 63.6% of BMT patients. The incidence of post-BMT TMA is affected by evolving therapies such as conditioning regimens. The etiology of post-BMT TMA is thought to be multifactorial, including the effects of immunosuppressive agents, viral infections, TBI and GvHD. A growing body of evidence highlights the importance of complement system activation and endothelial damage in post-BMT TMA. Although plasmapheresis has commonly been used, its therapeutic rationale for the majority of post-BMT TMA cases is unclear in the absence of circulatory inhibitors. It has become possible to target complement activation with eculizumab, a drug that blocks the terminal complement pathway. Early studies have highlighted the importance of anti-complement therapies in treating post-BMT TMA. Moreover, finding complement gene mutations may identify patients at risk, but whether such patients benefit from prophylactic anti-complement therapies before BMT remains to be studied. This review focuses on diagnostic criteria, pathophysiology, treatment and renal outcomes of post-BMT TMA. PMID:26974272

  6. Post-Traumatic Stress Disorder and Violence.

    ERIC Educational Resources Information Center

    French, Laurence

    This paper is a clinical discussion of post-traumatic stress disorder and violence, particularly as it applies to the Vietnam Post-Traumatic Stress Syndrome. In the first section, the syndrome is described as the sudden onset of explosive rage and unprovoked violence with little or no warning, accompanied by a drastic change in personality. It is…

  7. 10 CFR 1048.6 - Posting.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 10 Energy 4 2010-01-01 2010-01-01 false Posting. 1048.6 Section 1048.6 Energy DEPARTMENT OF ENERGY (GENERAL PROVISIONS) TRESPASSING ON STRATEGIC PETROLEUM RESERVE FACILITIES AND OTHER PROPERTY § 1048.6 Posting. Notices stating the pertinent prohibitions of §§ 1048.3 and 1048.4 and the penalties of §...

  8. 10 CFR 1048.6 - Posting.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 10 Energy 4 2011-01-01 2011-01-01 false Posting. 1048.6 Section 1048.6 Energy DEPARTMENT OF ENERGY (GENERAL PROVISIONS) TRESPASSING ON STRATEGIC PETROLEUM RESERVE FACILITIES AND OTHER PROPERTY § 1048.6 Posting. Notices stating the pertinent prohibitions of §§ 1048.3 and 1048.4 and the penalties of §...

  9. 42 CFR 124.604 - Posted notice.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false Posted notice. 124.604 Section 124.604 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES HEALTH RESOURCES DEVELOPMENT MEDICAL FACILITY CONSTRUCTION AND MODERNIZATION Community Service § 124.604 Posted notice. (a)...

  10. 42 CFR 124.604 - Posted notice.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 1 2012-10-01 2012-10-01 false Posted notice. 124.604 Section 124.604 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES HEALTH RESOURCES DEVELOPMENT MEDICAL FACILITY CONSTRUCTION AND MODERNIZATION Community Service § 124.604 Posted notice. (a)...

  11. 42 CFR 124.604 - Posted notice.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false Posted notice. 124.604 Section 124.604 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES HEALTH RESOURCES DEVELOPMENT MEDICAL FACILITY CONSTRUCTION AND MODERNIZATION Community Service § 124.604 Posted notice. (a)...

  12. 42 CFR 124.604 - Posted notice.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 1 2013-10-01 2013-10-01 false Posted notice. 124.604 Section 124.604 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES HEALTH RESOURCES DEVELOPMENT MEDICAL FACILITY CONSTRUCTION AND MODERNIZATION Community Service § 124.604 Posted notice. (a)...

  13. 76 FR 57086 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-15

    ... informs the public that an appeal of the closing of the Lincoln, Iowa post office has been filed. It... Postal Service's determination to close the Lincoln post office in Lincoln, Iowa. The petition was filed by the Citizens of Lincoln, Iowa (Petitioner) and is postmarked August 24, 2011. The...

  14. 10 CFR 34.53 - Posting.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 10 Energy 1 2011-01-01 2011-01-01 false Posting. 34.53 Section 34.53 Energy NUCLEAR REGULATORY COMMISSION LICENSES FOR INDUSTRIAL RADIOGRAPHY AND RADIATION SAFETY REQUIREMENTS FOR INDUSTRIAL RADIOGRAPHIC OPERATIONS Radiation Safety Requirements § 34.53 Posting. All areas in which industrial radiography is being performed must be...

  15. 10 CFR 34.53 - Posting.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 10 Energy 1 2010-01-01 2010-01-01 false Posting. 34.53 Section 34.53 Energy NUCLEAR REGULATORY COMMISSION LICENSES FOR INDUSTRIAL RADIOGRAPHY AND RADIATION SAFETY REQUIREMENTS FOR INDUSTRIAL RADIOGRAPHIC OPERATIONS Radiation Safety Requirements § 34.53 Posting. All areas in which industrial radiography is...

  16. Post-emergence herbicides useful in calendula

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Easy and effective weed control is required by growers who are considering new industrial crops. Post-emergence herbicides typically are the products of choice by today’s growers. Unfortunately, post-emergence herbicides with proven safety margins are not known for calendula (Calendula officinalis),...

  17. 76 FR 44383 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-07-25

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Rosser, Texas post office has been filed....

  18. 76 FR 17717 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-03-30

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Ida Post Office in Ida, Arkansas has been...

  19. 76 FR 57083 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-15

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Etna, New York post office has been filed....

  20. 46 CFR Sec. 4 - Posting of bond.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 46 Shipping 8 2011-10-01 2011-10-01 false Posting of bond. Sec. 4 Section 4 Shipping MARITIME ADMINISTRATION, DEPARTMENT OF TRANSPORTATION A-NATIONAL SHIPPING AUTHORITY BONDING OF SHIP'S PERSONNEL Sec. 4 Posting of bond. The General Agent shall retain an executed copy of each such bond in its principal...

  1. 46 CFR Sec. 4 - Posting of bond.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 8 2010-10-01 2010-10-01 false Posting of bond. Sec. 4 Section 4 Shipping MARITIME ADMINISTRATION, DEPARTMENT OF TRANSPORTATION A-NATIONAL SHIPPING AUTHORITY BONDING OF SHIP'S PERSONNEL Sec. 4 Posting of bond. The General Agent shall retain an executed copy of each such bond in its principal...

  2. 76 FR 66336 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-26

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Ardenvoir, Washington, post office has been filed... Commission received a petition for review of the Postal Service's determination to close the Ardenvoir...

  3. 76 FR 68234 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-03

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the McFarlan, North Carolina post office has been... Commission received a petition for review of the Postal Service's determination to close the McFarlan...

  4. 76 FR 68235 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-03

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Glencliff, New Hampshire post office has been... Commission received a petition for review of the Postal Service's determination to close the Glencliff...

  5. 76 FR 78953 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-20

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Mount Union, Iowa post office has been filed. It... Commission received two petitions for review of the Postal Service's determination to close the Mount...

  6. 76 FR 76452 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-07

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Porterville, Mississippi post office has been... Commission received a petition for review of the Postal Service's determination to close the Porterville...

  7. 76 FR 63331 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-12

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Lakeville, Connecticut post office has been filed... Commission received a petition for review of the Postal Service's determination to close the Lakeville...

  8. 76 FR 55138 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-06

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Fishers Landing, New York post office has been... received a petition for review of the Postal Service's determination to close the Fishers Landing...

  9. Academic Community and Post-Tenure Review.

    ERIC Educational Resources Information Center

    Tierney, William G.

    1997-01-01

    Discusses the need for post-tenure faculty review to root out "dead wood" faculty and increase faculty accountability, focusing on the time frame for such reviews, who gets reviewed, and the intensity and ramifications of the review. Also notes criticisms of post-tenure reviews and the need to build community through self-regulation. (MDM)

  10. 76 FR 61759 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-05

    ... From the Federal Register Online via the Government Publishing Office POSTAL REGULATORY COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Pimmit Branch, Falls Church, Virginia post...

  11. 77 FR 1750 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-11

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Elk River, Idaho post office has been filed. It... Commission received a petition for review of the Postal Service's determination to close the Elk River...

  12. 77 FR 7213 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-02-10

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Santa Fe, Missouri post office has been filed. It... Commission received two petitions for review of the Postal Service's determination to close the Santa Fe...

  13. 76 FR 76202 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-06

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Little America, Wyoming post office has been filed... received a petition for review of the Postal Service's determination to close the Little America...

  14. 76 FR 67000 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-28

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Jenkinjones, West Virginia post office has been... Commission received a petition for review of the Postal Service's determination to close the Jenkinjones...

  15. 77 FR 3808 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-25

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Chilo, Ohio post office has been filed. It... Commission received a petition for review of the Postal Service's determination to close the Chilo...

  16. 77 FR 3805 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-25

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Bovill, Idaho post office has been filed. It... Commission received three petitions for review of the Postal Service's determination to close the Bovill...

  17. 76 FR 62097 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-06

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the West Stockholm, New York post office has been... received a petition for review of the Postal Service's determination to close the West Stockholm...

  18. 76 FR 75917 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-05

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Fort Meade, South Dakota post office has been... Commission received a petition for review of the Postal Service's determination to close the Fort Meade...

  19. 76 FR 67002 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-28

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the New Hampton, Missouri post office has been filed... Commission received a petition for review of the Postal Service's determination to close the New Hampton...

  20. 77 FR 4383 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-27

    ... COMMISSION Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Elwell, Michigan post office has been filed. It... Commission received three petitions for review of the Postal Service's determination to close the Elwell...

  1. 77 FR 4381 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-27

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Peterson, Minnesota post office has been filed. It... Commission received a petition for review of the Postal Service's determination to close the Peterson...

  2. 77 FR 4377 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-27

    ... Post Office Closing AGENCY: Postal Regulatory Commission. ACTION: Notice. SUMMARY: This document informs the public that an appeal of the closing of the Randolph, Iowa post office has been filed. It... Commission received a petition for review of the Postal Service's determination to close the Randolph...

  3. 76 FR 58057 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-19

    ... informs the public that an appeal of the closing of the Burnt Prairie, Illinois post office has been filed... for review of the Postal Service's determination to close the Burnt Prairie post office in Burnt Prairie, Illinois. The petition was filed by Steven L. Whetstone (Petitioner) and is postmarked August...

  4. 46 CFR 169.217 - Posting.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 46 Shipping 7 2013-10-01 2013-10-01 false Posting. 169.217 Section 169.217 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) NAUTICAL SCHOOLS SAILING SCHOOL VESSELS Inspection and Certification Certificate of Inspection § 169.217 Posting. The certificate of inspection must be framed...

  5. 46 CFR 169.217 - Posting.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 46 Shipping 7 2012-10-01 2012-10-01 false Posting. 169.217 Section 169.217 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) NAUTICAL SCHOOLS SAILING SCHOOL VESSELS Inspection and Certification Certificate of Inspection § 169.217 Posting. The certificate of inspection must be framed...

  6. 46 CFR 169.217 - Posting.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 46 Shipping 7 2014-10-01 2014-10-01 false Posting. 169.217 Section 169.217 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) NAUTICAL SCHOOLS SAILING SCHOOL VESSELS Inspection and Certification Certificate of Inspection § 169.217 Posting. The certificate of inspection must be framed...

  7. 46 CFR 169.217 - Posting.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 46 Shipping 7 2011-10-01 2011-10-01 false Posting. 169.217 Section 169.217 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) NAUTICAL SCHOOLS SAILING SCHOOL VESSELS Inspection and Certification Certificate of Inspection § 169.217 Posting. The certificate of inspection must be framed...

  8. 46 CFR 169.217 - Posting.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 7 2010-10-01 2010-10-01 false Posting. 169.217 Section 169.217 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) NAUTICAL SCHOOLS SAILING SCHOOL VESSELS Inspection and Certification Certificate of Inspection § 169.217 Posting. The certificate of inspection must be framed...

  9. 10 CFR 76.70 - Post issuance.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 10 Energy 2 2011-01-01 2011-01-01 false Post issuance. 76.70 Section 76.70 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) CERTIFICATION OF GASEOUS DIFFUSION PLANTS Certification § 76.70 Post issuance. (a) Amendment of certificate terms and conditions. The terms and conditions of a certificate...

  10. 10 CFR 76.70 - Post issuance.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 10 Energy 2 2013-01-01 2013-01-01 false Post issuance. 76.70 Section 76.70 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) CERTIFICATION OF GASEOUS DIFFUSION PLANTS Certification § 76.70 Post issuance. (a) Amendment of certificate terms and conditions. The terms and conditions of a certificate...

  11. 10 CFR 76.70 - Post issuance.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 10 Energy 2 2012-01-01 2012-01-01 false Post issuance. 76.70 Section 76.70 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) CERTIFICATION OF GASEOUS DIFFUSION PLANTS Certification § 76.70 Post issuance. (a) Amendment of certificate terms and conditions. The terms and conditions of a certificate...

  12. 10 CFR 76.70 - Post issuance.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 10 Energy 2 2010-01-01 2010-01-01 false Post issuance. 76.70 Section 76.70 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) CERTIFICATION OF GASEOUS DIFFUSION PLANTS Certification § 76.70 Post issuance. (a) Amendment of certificate terms and conditions. The terms and conditions of a certificate...

  13. 10 CFR 76.70 - Post issuance.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 10 Energy 2 2014-01-01 2014-01-01 false Post issuance. 76.70 Section 76.70 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) CERTIFICATION OF GASEOUS DIFFUSION PLANTS Certification § 76.70 Post issuance. (a) Amendment of certificate terms and conditions. The terms and conditions of a certificate...

  14. Retention of Root Canal Posts: Effect of Cement Film Thickness, Luting Cement, and Post Pretreatment.

    PubMed

    Sahafi, A; Benetti, A R; Flury, S; Peutzfeldt, A

    2015-01-01

    The aim of this study was to investigate the effect of the cement film thickness of a zinc phosphate or a resin cement on retention of untreated and pretreated root canal posts. Prefabricated zirconia posts (CosmoPost: 1.4 mm) and two types of luting cements (a zinc phosphate cement [DeTrey Zinc] and a self-etch adhesive resin cement [Panavia F2.0]) were used. After removal of the crowns of 360 extracted premolars, canines, or incisors, the root canals were prepared with a parallel-sided drill system to three different final diameters. Half the posts did not receive any pretreatment. The other half received tribochemical silicate coating according to the manufacturer's instructions. Posts were then luted in the prepared root canals (n=30 per group). Following water storage at 37°C for seven days, retention of the posts was determined by the pull-out method. Irrespective of the luting cement, pretreatment with tribochemical silicate coating significantly increased retention of the posts. Increased cement film thickness resulted in decreased retention of untreated posts and of pretreated posts luted with zinc phosphate cement. Increased cement film thickness had no influence on retention of pretreated posts luted with resin cement. Thus, retention of the posts was influenced by the type of luting cement, by the cement film thickness, and by the post pretreatment. PMID:25764045

  15. Interventional Treatment for Post-traumatic Headache.

    PubMed

    Conidi, Francis X

    2016-06-01

    Post-traumatic headache (migraine) is the most common symptom of concussion and traumatic brain injury. An expert opinion-based review along with a literature review (PubMed) was conducted looking at known interventional procedures for post-traumatic headache using the keywords post-traumatic headache, post-traumatic migraine headache, concussion, mild traumatic brain injury, and traumatic brain injury and the following categories: mechanism, pathophysiology, treatment, physical therapy, neurostimulation, Botox@/Onabotulinum toxin, and surgical intervention. The results returned a total of 181 articles of which 52 were selected. None of the articles included randomized placebo-controlled studies, and most were either prospective or retrospective case analysis and/or review articles or consensus opinion papers, with most studies yielding positive results. Despite a lack of hard evidence, interventional procedures, alone or in combination, appear to be an effective treatment for post-traumatic headaches. PMID:27130542

  16. Fiber post techniques for anatomical root variations.

    PubMed

    Boksman, Leendert; Hepburn, Alejandro Bertoldi; Kogan, Enrique; Friedman, Manny; de Rijk, Waldemar

    2011-05-01

    In contemporary dental practice, there is no remaining reason to use metallic posts, custom or prefabricated. Many cases that several years ago would have required a retentive post will not require that post today, because of the many improvements in bonding agents and composite resin restoratives. However, in cases where less than 50% of coronal tooth structure remains--or in other cases wherein the judgment of the clinician a post is indicated--there are now aesthetic, non-corrosive, fracture resistant and radiopaque alternatives for all varieties that save time and money without compromise. Their most compelling advantage, regardless of the geometry or amount of residual tooth structure, is the protection from root fracture that a low modulus restoration provides. In selecting the materials (posts, resins) for these techniques, the dentist is advised not to cut corners, and to seek the strongest and most radiopaque products available. PMID:21650123

  17. CID Post-impact fireball

    NASA Technical Reports Server (NTRS)

    1984-01-01

    Following its controlled impact on posts imbedded in the lakebed, the B-720 is sliding sideways and almost enveloped in the large fireball with only the aircraft's nose and right wing-tip exposed. In a typical aircraft crash, fuel spilled from ruptured fuel tanks forms a fine mist that can be ignited by a number of sources at the crash site. In 1984 the NASA Dryden Flight Research Facility (after 1994 a full-fledged Center again) and the Federal Aviation Administration (FAA) teamed-up in a unique flight experiment called the Controlled Impact Demonstration (CID), to test crash a Boeing 720 aircraft using standard fuel with an additive designed to supress fire. The additive, FM-9, a high-molecular-weight long-chain polymer, when blended with Jet-A fuel had demonstrated the capability to inhibit ignition and flame propagation of the released fuel in simulated crash tests. This anti-misting kerosene (AMK) cannot be introduced directly into a gas turbine engine due to several possible problems such as clogging of filters. The AMK must be restored to almost Jet-A before being introduced into the engine for burning. This restoration is called 'degradation' and was accomplished on the B-720 using a device called a 'degrader.' Each of the four Pratt & Whitney JT3C-7 engines had a 'degrader' built and installed by General Electric (GE) to break down and return the AMK to near Jet-A quality. In addition to the AMK research the NASA Langley Research Center was involved in a structural loads measurement experiment, which included having instrumented dummies filling the seats in the passenger compartment. Before the final flight on December 1, 1984, more than four years of effort passed trying to set-up final impact conditions considered survivable by the FAA. During those years while 14 flights with crews were flown the following major efforts were underway: NASA Dryden developed the remote piloting techniques necessary for the B-720 to fly as a drone aircraft; General

  18. Post-Retrofit Residential Assessments

    SciTech Connect

    Lancaster, Ross; lutzenhiser, Loren; Moezzi, Mithra; Widder, Sarah H.; Chandra, Subrato; Baechler, Michael C.

    2012-04-30

    This study examined a range of factors influencing energy consumption in households that had participated in residential energy-efficiency upgrades. The study was funded by a grant from the U.S. Department of Energy’s Pacific Northwest National Laboratory and was conducted by faculty and staff of Portland State University Center for Urban Studies and Department of Economics. This work was made possible through the assistance and support of the Energy Trust of Oregon (ETO), whose residential energy-efficiency programs provided the population from which the sample cases were drawn. All households in the study had participated in the ETO Home Performance with Energy Star (HPwES) program. A number of these had concurrently pursued measures through other ETO programs. Post-retrofit energy outcomes are rarely investigated on a house-by-house basis. Rather, aggregate changes are ordinarily the focus of program impact evaluations, with deviation from aggregate expectations chalked up to measurement error, the vagaries of weather and idiosyncrasies of occupants. However, understanding how homes perform post-retrofit on an individual basis can give important insights to increase energy savings at the participant and the programmatic level. Taking a more disaggregated approach, this study analyzed energy consumption data from before and after the retrofit activity and made comparisons with engineering estimates for the upgrades, to identify households that performed differently from what may have been expected based on the estimates. A statistical analysis using hierarchal linear models, which accounted for weather variations, was performed looking separately at gas and electrical use during the periods before and after upgrades took place. A more straightforward comparison of billing data for 12-month periods before and after the intervention was also performed, yielding the majority of the cases examined. The later approach allowed total energy use and costs to be

  19. Explosive signatures: Pre & post blast

    NASA Astrophysics Data System (ADS)

    Bernier, Evan Thomas

    Manuscripts 1 and 2 of this dissertation both involve the pre-blast detection of trace explosive material. The first manuscript explores the analysis of human hair as an indicator of exposure to explosives. Field analysis of hair for trace explosives is quick and non-invasive, and could prove to be a powerful linkage to physical evidence in the form of bulk explosive material. Individuals tested were involved in studies which required handling or close proximity to bulk high explosives such as TNT, PETN, and RDX. The second manuscript reports the results of research in the design and application of canine training aids for non-traditional, peroxide-based explosives. Organic peroxides such as triacetonetriperoxide (TATP) and hexamethylenetriperoxidediamine (HMTD) can be synthesized relatively easily with store-bought ingredients and have become popular improvised explosives with many terrorist groups. Due to the hazards of handling such sensitive compounds, this research established methods for preparing training aids which contained safe quantities of TATP and HMTD for use in imprinting canines with their characteristic odor. Manuscripts 3 and 4 of this dissertation focus on research conducted to characterize pipe bombs during and after an explosion (post-blast). Pipe bombs represent a large percentage of domestic devices encountered by law enforcement. The current project has involved the preparation and controlled explosion of over 90 pipe bombs of different configurations in order to obtain data on fragmentation patterns, fragment velocity, blast overpressure, and fragmentation distance. Physical data recorded from the collected fragments, such as mass, size, and thickness, was correlated with the relative power of the initial device. Manuscript 4 explores the microstructural analysis of select pipe bomb fragments. Shock-loading of the pipe steel led to plastic deformation and work hardening in the steel grain structure as evidenced by optical microscopy and

  20. Development of new radiopaque glass fiber posts.

    PubMed

    Furtos, Gabriel; Baldea, Bogdan; Silaghi-Dumitrescu, Laura

    2016-02-01

    The aim of this study was to analyze the radiopacity and filler content of three experimental glass fiber posts (EGFP) in comparison with other glass/carbon fibers and metal posts from the dental market. Three EGFP were obtained by pultrusion of glass fibers in a polymer matrix based on 2,2-bis[4-(2-hydroxy-3-methacryloyloxypropoxy)-phenyl]propane (bis-GMA) and triethyleneglycol dimethacrylate (TEGDMA) monomers. Using intraoral sensor disks 27 posts, as well as mesiodistal sections of human molar and aluminum step wedges were radiographed for evaluation of radiopacity. The percentage compositions of fillers by weight and volume were investigated by combustion analysis. Two EGFP showed radiopacity higher than enamel. The commercial endodontic posts showed radiopacity as follows: higher than enamel, between enamel and dentin, and lower than dentin. The results showed statistically significant differences (p b 0.05)when evaluatedwith one-way ANOVA statistical analysis. According to combustion analyses, the filler content of the tested posts ranges between 58.84wt.% and 86.02wt.%. The filler content of the tested EGFP ranged between 68.91 wt.% and 79.04 wt.%. EGFP could be an alternative to commercial glass fiber posts. Futureglass fiber posts are recommended to present higher radiopacity than dentin and perhaps ideally similar to or higher than that of enamel, for improved clinical detection. The posts with a lower radiopacity than dentin should be considered insufficiently radiopaque. The radiopacity of some glass fiber posts is not greatly influenced by the amount of filler. PMID:26652441

  1. Post-dengue encephalopathy and Parkinsonism.

    PubMed

    Fong, Choong Yi; Hlaing, Chaw Su; Tay, Chee Geap; Ong, Lai Choo

    2014-10-01

    Parkinsonism as a neurologic manifestation of dengue infection is rare with only 1 reported case in an adult patient. We report a case of a 6-year-old child with self-limiting post-dengue encephalopathy and Parkinsonism. This is the first reported pediatric case of post-dengue Parkinsonism and expands the neurologic manifestations associated with dengue infection in children. Clinicians should consider the possibility of post-dengue Parkinsonism in children with a history of pyrexia from endemic areas of dengue. PMID:24776518

  2. Post-Genomics and Skin Inflammation

    PubMed Central

    Braconi, Daniela; Bernardini, Giulia; Santucci, Annalisa

    2010-01-01

    Atopic dermatitis and psoriasis are two chronic skin inflammatory diseases that have so far received a greater attention within the scientific community through different post-genomic approaches; on the contrary, acne, which is undoubtedly one of the most common skin disorders involving inflammatory processes, seems to be still quite neglected under the post-genomic point of view. In this paper, we will review how post-genomic technologies have provided new fundamental tools for the analysis of these three conditions and we will cast light on their potential in addressing future research challenges. PMID:20886018

  3. Post-genomics and skin inflammation.

    PubMed

    Braconi, Daniela; Bernardini, Giulia; Santucci, Annalisa

    2010-01-01

    Atopic dermatitis and psoriasis are two chronic skin inflammatory diseases that have so far received a greater attention within the scientific community through different post-genomic approaches; on the contrary, acne, which is undoubtedly one of the most common skin disorders involving inflammatory processes, seems to be still quite neglected under the post-genomic point of view. In this paper, we will review how post-genomic technologies have provided new fundamental tools for the analysis of these three conditions and we will cast light on their potential in addressing future research challenges. PMID:20886018

  4. Evaluation of pre-fabricated root canal posts.

    PubMed

    Hew, Y S; Purton, D G; Love, R M

    2001-03-01

    In this in vitro study, properties of a titanium alloy post recently introduced to the market (IntegraPost), were compared with those of a clinically proven stainless steel post (ParaPost). The IntegraPost has a unique, perforated, spherical head and a microknurled shank surface. The posts were tested for rigidity, for retention within the root canals of extracted teeth and for ability to retain composite resin cores. The two post types exhibited similar properties in core and root canal retention, however, the IntegraPost was significantly less rigid than the ParaPost. PMID:11350574

  5. 49 CFR 663.39 - Post-delivery audit review.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 7 2011-10-01 2011-10-01 false Post-delivery audit review. 663.39 Section 663.39..., DEPARTMENT OF TRANSPORTATION PRE-AWARD AND POST-DELIVERY AUDITS OF ROLLING STOCK PURCHASES Post-Delivery Audits § 663.39 Post-delivery audit review. (a) If a recipient cannot complete a post-delivery...

  6. 49 CFR 663.39 - Post-delivery audit review.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 7 2014-10-01 2014-10-01 false Post-delivery audit review. 663.39 Section 663.39..., DEPARTMENT OF TRANSPORTATION PRE-AWARD AND POST-DELIVERY AUDITS OF ROLLING STOCK PURCHASES Post-Delivery Audits § 663.39 Post-delivery audit review. (a) If a recipient cannot complete a post-delivery...

  7. 49 CFR 663.39 - Post-delivery audit review.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 7 2012-10-01 2012-10-01 false Post-delivery audit review. 663.39 Section 663.39..., DEPARTMENT OF TRANSPORTATION PRE-AWARD AND POST-DELIVERY AUDITS OF ROLLING STOCK PURCHASES Post-Delivery Audits § 663.39 Post-delivery audit review. (a) If a recipient cannot complete a post-delivery...

  8. 49 CFR 663.39 - Post-delivery audit review.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 7 2013-10-01 2013-10-01 false Post-delivery audit review. 663.39 Section 663.39..., DEPARTMENT OF TRANSPORTATION PRE-AWARD AND POST-DELIVERY AUDITS OF ROLLING STOCK PURCHASES Post-Delivery Audits § 663.39 Post-delivery audit review. (a) If a recipient cannot complete a post-delivery...

  9. Post-traumatic Stress Disorder.

    PubMed

    Javidi, H; Yadollahie, M

    2012-01-01

    Unexpected extreme sudden traumatic stressor may cause post-traumatic stress disorder (PTSD). Important traumatic events include war, violent personal assault (e.g., sexual assault, and physical attack), being taken hostage or kidnapped, confinement as a prisoner of war, torture, terrorist attack, severe car accidents, and natural disasters. In childhood age sexual abuse or witnessing serious injuries or unexpected death of a beloved one are among important traumatic events.PTSD can be categorized into two types of acute and chronic PTSD: if symptoms persist for less than three months, it is termed "acute PTSD," otherwise, it is called "chronic PTSD." 60.7% of men and 51.2% of women would experience at least one potentially traumatic event in their lifetime. The lifetime prevalence of PTSD is significantly higher in women than men. Lifetime prevalence of PTSD varies from 0.3% in China to 6.1% in New Zealand. The prevalence of PTSD in crime victims are between 19% and 75%; rates as high as 80% have been reported following rape. The prevalence of PTSD among direct victims of disasters was reported to be 30%-40%; the rate in rescue workers was 10%-20%. The prevalence of PTSD among police, fire, and emergency service workers ranged from 6%-32%. An overall prevalence rate of 4% for the general population, the rate in rescue/recovery occupations ranged from 5% to 32%, with the highest rate reported in search and rescue personnel (25%), firefighters (21%), and workers with no prior training for facing disaster. War is one of the most intense stressors known to man. Armed forces have a higher prevalence of depression, anxiety disorders, alcohol abuse and PTSD. High-risk children who have been abused or experienced natural disasters may have an even higher prevalence of PTSD than adults.Female gender, previous psychiatric problem, intensity and nature of exposure to the traumatic event, and lack of social support are known risk factors for work-related PTSD. Working with

  10. CID Post-impact fireball

    NASA Technical Reports Server (NTRS)

    1984-01-01

    four degraders (one on each engine); and the FAA refined AMK (blending, testing, and fueling a full-size aircraft). The 15 flights had 15 takeoffs, 14 landings and a larger number of approaches to about 150 feet above the prepared crash site under remote control. These flight were used to introduce AMK one step at a time into some of the fuel tanks and engines while monitoring the performance of the engines. On the final flight (No. 15) with no crew, all fuel tanks were filled with a total of 76,000 pounds of AMK and the remotely-piloted aircraft landed on Rogers Dry Lakebed in an area prepared with posts to test the effectiveness of the AMK in a controlled impact. The CID, which some wags called the Crash in the Desert, was spectacular with a large fireball enveloping and burning the B-720 aircraft. From the standpoint of AMK the test was a major set-back, but for NASA Langley, the data collected on crashworthiness was deemed successful and just as important.

  11. Post-stroke language disorders.

    PubMed

    Sinanović, Osman; Mrkonjić, Zamir; Zukić, Sanela; Vidović, Mirjana; Imamović, Kata

    2011-03-01

    Post-stroke language disorders are frequent and include aphasia, alexia, agraphia and acalculia. There are different definitions of aphasias, but the most widely accepted neurologic and/or neuropsychological definition is that aphasia is a loss or impairment of verbal communication, which occurs as a consequence of brain dysfunction. It manifests as impairment of almost all verbal abilities, e.g., abnormal verbal expression, difficulties in understanding spoken or written language, repetition, naming, reading and writing. During the history, many classifications of aphasia syndromes were established. For practical use, classification of aphasias according to fluency, comprehension and abilities of naming it seems to be most suitable (nonfluent aphasias: Broca's, transcortical motor, global and mixed transcortical aphasia; fluent aphasias: anomic, conduction, Wernicke's, transcortical sensory, subcortical aphasia). Aphasia is a common consequence of left hemispheric lesion and most common neuropsychological consequence of stroke, with a prevalence of one-third of all stroke patients in acute phase, although there are reports on even higher figures. Many speech impairments have a tendency of spontaneous recovery. Spontaneous recovery is most remarkable in the first three months after stroke onset. Recovery of aphasias caused by ischemic stroke occurs earlier and it is most intensive in the first two weeks. In aphasias caused by hemorrhagic stroke, spontaneous recovery is slower and occurs from the fourth to the eighth week after stroke. The course and outcome of aphasia depend greatly on the type of aphasia. Regardless of the fact that a significant number of aphasias spontaneously improve, it is necessary to start treatment as soon as possible. The writing and reading disorders in stroke patients (alexias and agraphias) are more frequent than verified on routine examination, not only in less developed but also in large neurologic departments. Alexia is an acquired

  12. 23. INCLINED END POST / VERTICAL / DIAGONAL / PORTAL ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    23. INCLINED END POST / VERTICAL / DIAGONAL / PORTAL BRACING DETAIL. VIEW TO SOUTHEAST. - Abraham Lincoln Memorial Bridge, Spanning Missouri River on Highway 30 between Nebraska & Iowa, Blair, Washington County, NE

  13. 76 FR 60561 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-29

    ... section as the source for case-related information for advice on alternatives to electronic filing. FOR... petition for review of the Postal Service's determination to close the Clarksville post office...

  14. Apollo 13 Facts [Post Flight Press Conference

    NASA Technical Reports Server (NTRS)

    2001-01-01

    The Apollo 13 astronauts, James Lovell, Jr., John Swigert, Jr., and Fred Haise, Jr., are seen during this post flight press conference. They describe their mission and answer questions from the audience.

  15. Apollo 13 Facts [Post Mission Honorary Ceremony

    NASA Technical Reports Server (NTRS)

    2001-01-01

    The Apollo 13 astronauts, James Lovell, Jr., John Swigert, Jr., and Fred Haise, Jr., are seen during this post mission honorary ceremony, led by President Richard Nixon. Lovell is shown during an interview, answering questions about the mission.

  16. Post-Treatment Lyme Disease Syndrome

    MedlinePlus

    ... FAQ Health care providers Educational materials Post-Treatment Lyme Disease Syndrome Recommend on Facebook Tweet Share Compartir It ... ONE 7(1): e29914. HHS Special Webinar on Lyme Disease Persistence frame support disabled and/or not supported ...

  17. 76 FR 53159 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-08-25

    ... Earlene Cannon on behalf of the Committee to Save Ida Post Office (Petitioner) and is postmarked August 9.... Intervention. Persons, other than Petitioner and respondent, wishing to be heard in this matter are directed...

  18. Post-operative pulmonary complications after thoracotomy

    PubMed Central

    Sengupta, Saikat

    2015-01-01

    Pulmonary complications are a major cause of morbidity and mortality in the post-operative period after thoracotomy. The type of complications and the severity of complications depend on the type of thoracic surgery that has been performed as well as on the patient's pre-operative medical status. Risk stratification can help in predicting the possibility of the post-operative complications. Certain airway complications are more prone to develop with thoracic surgery. Vocal cord injuries, bronchopleural fistulae, pulmonary emboli and post-thoracic surgery non-cardiogenic pulmonary oedema are some of the unique complications that occur in this subset of patients. The major pulmonary complications such as atelectasis, bronchospasm and pneumonia can lead to respiratory failure. This review was compiled after a search for search terms within ‘post-operative pulmonary complications after thoracic surgery and thoracotomy’ on search engines including PubMed and standard text references on the subject from 2000 to 2015. PMID:26556921

  19. 76 FR 60562 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-29

    ... section as the source for case-related information for advice on alternatives to electronic filing. FOR... petitions for review of the Postal Service's determination to close the Tariffville post office...

  20. 76 FR 57768 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-16

    ... electronically should contact the person identified in the FOR FURTHER INFORMATION CONTACT section as the source... Postal Service's determination to close the Sharpsburg post office in Sharpsburg, Iowa. The petition...

  1. 76 FR 57767 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-16

    ... electronically should contact the person identified in the FOR FURTHER INFORMATION CONTACT section as the source... Postal Service's determination to close the Ionia post office in Ionia, Missouri. The petition was...

  2. 76 FR 59749 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-27

    ... section as the source for case-related information for advice on alternatives to electronic filing. FOR... petition for review of the Postal Service's determination to close the Martinsburg post office...

  3. 76 FR 72728 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-25

    ... INFORMATION CONTACT section as the source for case-related information for advice on alternatives to... petitions for review of the Postal Service's determination to close the Swaledale post office in...

  4. 76 FR 49800 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-08-11

    ... electronically should contact the person identified in the FOR FURTHER INFORMATION CONTACT section as the source... Postal Service's determination to close the post office in Masonville, Iowa. The petition was filed...

  5. 76 FR 48924 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-08-09

    ... electronically should contact the person identified in the FOR FURTHER INFORMATION CONTACT section as the source... Service's determination to close the post office in Thayer, Iowa. The petition was filed by Mike...

  6. 76 FR 59453 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-26

    ... section as the source for case-related information for advice on alternatives to electronic filing. FOR... petition for review of the Postal Service's determination to close the Ellisburg post office in...

  7. 76 FR 49801 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-08-11

    ... electronically should contact the person identified in the FOR FURTHER INFORMATION CONTACT section as the source... Postal Service's determination to close the post office in Monroe, Arkansas. The petition was filed...

  8. 76 FR 51436 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-08-18

    ... electronically should contact the person identified in the FOR FURTHER INFORMATION CONTACT section as the source... Postal Service's determination to close the post office in Sublime, Texas. The petition was filed...

  9. 76 FR 49799 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-08-11

    ... electronically should contact the person identified in the FOR FURTHER INFORMATION CONTACT section as the source... Postal Service's determination to close the post office in Ulman, Missouri. The petition was filed...

  10. 76 FR 60559 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-29

    ... electronically should contact the person identified in the FOR FURTHER INFORMATION CONTACT section as the source... Postal Service's determination to close the Smyrna post office in Smyrna, New York. The petition...

  11. 76 FR 60563 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-29

    ... electronically should contact the person identified in the FOR FURTHER INFORMATION CONTACT section as the source... Postal Service's determination to close the Algoma post office in Algoma, Mississippi. The petition...

  12. 76 FR 59452 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-26

    ... electronically should contact the person identified in the FOR FURTHER INFORMATION CONTACT section as the source... Postal Service's determination to close the Ellisburg post office in Ellisburg, New York. The...

  13. 76 FR 76774 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-08

    ... INFORMATION CONTACT section as the source for case-related information for advice on alternatives to... received a petition for review of the Postal Service's determination to close the Spring Lake post...

  14. 76 FR 58314 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-20

    ... section as the source for case-related information for advice on alternatives to electronic filing. FOR... for review of the Postal Service's determination to close the Board Camp post office in Board...

  15. 76 FR 48923 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-08-09

    ... electronically should contact the person identified in the FOR FURTHER INFORMATION CONTACT section as the source... Service's determination to close the post office in Hoxie, Arkansas. The petition was filed by...

  16. 76 FR 72727 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-25

    ... INFORMATION CONTACT section as the source for case-related information for advice on alternatives to... received a petition for review of the Postal Service's determination to close the Lafayette post office...

  17. 76 FR 51435 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-08-18

    ... electronically should contact the person identified in the FOR FURTHER INFORMATION CONTACT section as the source... Postal Service's determination to close the post office in Grant, Iowa. The petition was filed...

  18. 76 FR 58312 - Post Office Closing

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-20

    ... section as the source for case-related information for advice on alternatives to electronic filing. FOR... for review of the Postal Service's determination to close the Old Chatham post office in Old...

  19. Cloverleaf Vibratory Microgyroscope with Integrated Post

    NASA Technical Reports Server (NTRS)

    Tang, Tony K.; Gutierrez, Roman; Roger, Damien

    2003-01-01

    A modified design and fabrication sequence has been devised to improve the performance of a cloverleaf vibratory microgyroscope that includes an axial rod or post rigidly attached to the center of the cloverleaf structure. The basic concepts of cloverleaf vibratory microgyroscopes, without and with rods or posts, were described in two prior articles in NASA Tech Briefs, Vol. 21, No. 9 (September 1997): Micromachined Planar Vibratory Microgyroscopes (NPO-19713), page 68 and Planar Vibratory Microgyroscope: Alternative Configuration (NPO-19714), page 70. As described in more detail in the second-mentioned prior article, the cloverleaf-shaped structure and the rod or post are parts of a vibratory element that senses rotation via the effect of the Coriolis force upon its vibrations. Heretofore, the posts for devices of this type have been fabricated separately, then assembled manually onto the cloverleaf structures. The resulting imperfections in the assembled units have given rise to asymmetric stresses in the cloverleaf structures and, consequently, to changes in resonant frequencies of vibration and in shapes of vibration modes. These changes, in turn, have caused variations in performance among nominally identical devices. The modified design provides for the fabrication of the upper half of the post as an integral part of the cloverleaf structure; this is accomplished by reactive-ion etching of a single-piece half-post-and-cloverleaf structure from a wafer of silicon. The lower half of the post and a baseplate are also a single piece made by reactive-ion etching from a wafer of silicon. The two pieces are bonded together (see figure) by a thermal-compression metal-to-metal bonding technique to form a cloverleaf gyroscope with an integrated post structure..

  20. Content analysis of cancer blog posts*

    PubMed Central

    Kim, Sujin

    2009-01-01

    Objectives: The efficacy of user-defined subject tagging and software-generated subject tagging for describing and organizing cancer blog contents was explored. Methods: The Technorati search engine was used to search the blogosphere for cancer blog postings generated during a two-month period. Postings were mined for relevant subject concepts, and blogger-defined tags and Text Analysis Portal for Research (TAPoR) software–defined tags were generated for each message. Descriptive data were collected, and the blogger-defined tags were compared with software-generated tags. Three standard vocabularies (Opinion Templates, Basic Resource, and Medical Subject Headings [MeSH] Resource) were used to assign subject terms to the blogs, with results compared for efficacy in information retrieval. Results: Descriptive data showed that most of the studied cancer blogs (80%) contained fewer than 500 words each. The numbers of blogger-defined tags per posting (M = 4.49 per posting) were significantly smaller than the TAPoR keywords (M = 23.55 per posting). Both blogger-defined subject tags and software-generated subject tags were often overly broad or overly narrow in focus, producing less than effective search results for those seeking to extract information from cancer blogs. Conclusions: Additional exploration into methods for systematically organizing cancer blog postings is necessary if blogs are to become stable and efficacious information resources for cancer patients, friends, families, or providers. PMID:19851489