2018-03-28
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
Passamonti, F; Giorgino, T; Mora, B; Guglielmelli, P; Rumi, E; Maffioli, M; Rambaldi, A; Caramella, M; Komrokji, R; Gotlib, J; Kiladjian, J J; Cervantes, F; Devos, T; Palandri, F; De Stefano, V; Ruggeri, M; Silver, R T; Benevolo, G; Albano, F; Caramazza, D; Merli, M; Pietra, D; Casalone, R; Rotunno, G; Barbui, T; Cazzola, M; Vannucchi, A M
2017-12-01
Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms with variable risk of evolution into post-PV and post-ET myelofibrosis, from now on referred to as secondary myelofibrosis (SMF). No specific tools have been defined for risk stratification in SMF. To develop a prognostic model for predicting survival, we studied 685 JAK2, CALR, and MPL annotated patients with SMF. Median survival of the whole cohort was 9.3 years (95% CI: 8-not reached-NR-). Through penalized Cox regressions we identified negative predictors of survival and according to beta risk coefficients we assigned 2 points to hemoglobin level <11 g/dl, to circulating blasts ⩾3%, and to CALR-unmutated genotype, 1 point to platelet count <150 × 10 9 /l and to constitutional symptoms, and 0.15 points to any year of age. Myelofibrosis Secondary to PV and ET-Prognostic Model (MYSEC-PM) allocated SMF patients into four risk categories with different survival (P<0.0001): low (median survival NR; 133 patients), intermediate-1 (9.3 years, 95% CI: 8.1-NR; 245 patients), intermediate-2 (4.4 years, 95% CI: 3.2-7.9; 126 patients), and high risk (2 years, 95% CI: 1.7-3.9; 75 patients). Finally, we found that the MYSEC-PM represents the most appropriate tool for SMF decision-making to be used in clinical and trial settings.
Ikeda, Kazuhiko; Ueda, Koki; Sano, Takahiro; Ogawa, Kazuei; Ikezoe, Takayuki; Hashimoto, Yuko; Morishita, Soji; Komatsu, Norio; Ohto, Hitoshi; Takeishi, Yasuchika
2017-01-01
Less than 5% of patients with polycythemia vera (PV) show JAK2 exon 12 mutations. Although PV patients with JAK2 exon 12 mutations are known to develop post-PV myelofibrosis (MF) as well as PV with JAK2V617F, the role of JAK inhibitors in post-PV MF patients with JAK2 exon 12 mutations remains unknown. We describe how treatment with a JAK1/2 inhibitor, ruxolitinib, led to the rapid amelioration of marrow fibrosis, erythrocytosis and thrombocytopenia in a 77-year-old man with post-PV MF who carried a JAK2 exon 12 mutation (JAK2H538QK539L). This case suggests that ruxolitinib is a treatment option for post-PV MF in patients with thrombocytopenia or JAK2 exon 12 mutations.
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
Ruxolitinib for the treatment of myelofibrosis: a NICE single technology appraisal.
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.
... spleen Easy bruising Easy bleeding Excessive sweating during sleep (night sweats) Fever Bone pain When to see a doctor Make an appointment with your doctor if you have any persistent signs and symptoms that worry you. Causes Myelofibrosis occurs when blood stem cells develop a ...
Twin troubles--rickets causing myelofibrosis.
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.
Management of Myelofibrosis-Related Cytopenias.
Bose, Prithviraj; Verstovsek, Srdan
2018-05-23
Cytopenias, particularly anemia, are frequently encountered in patients with myelofibrosis. Management of cytopenias in myelofibrosis can be very challenging because current therapeutic interventions are only of modest efficacy and ruxolitinib, the only approved drug for myelofibrosis, is myelosuppressive. Yet, dose optimization of ruxolitinib is important for its survival benefit in patients with advanced disease. We sought to summarize the data on treatments for cytopenias available at present and review promising agents in development and emerging strategies. The activin receptor ligand traps hold considerable promise for the treatment of anemia and could represent an attractive combination strategy with ruxolitinib. Low-dose thalidomide, which could offset both anemia and thrombocytopenia caused by ruxolitinib, represents another potential partner for ruxolitinib. The anti-fibrotic agent PRM-151 produced sustained improvements in cytopenias in some patients, and further data on this drug are eagerly awaited. Finally, several preclinical leads with translational potential are worthy of clinical investigation as strategies to halt/reverse bone marrow fibrosis and thereby improve cytopenias. Cytopenias remain a significant hurdle in myelofibrosis management, but several novel investigational agents hold considerable promise for the future.
... are described below. Chronic myeloproliferative neoplasms sometimes become acute leukemia , in which too many abnormal white blood ... higher. Patients also have an increased risk of acute myeloid leukemia or primary myelofibrosis . Symptoms of polycythemia ...
β-Arrestin2 mediates progression of murine primary myelofibrosis.
Rein, Lindsay Am; Wisler, James W; Kim, Jihee; Theriot, Barbara; Huang, LiYin; Price, Trevor; Yang, Haeyoon; Chen, Minyong; Chen, Wei; Sipkins, Dorothy; Fedoriw, Yuri; Walker, Julia Kl; Premont, Richard T; Lefkowitz, Robert J
2017-12-21
Primary myelofibrosis is a myeloproliferative neoplasm associated with significant morbidity and mortality, for which effective therapies are lacking. β-Arrestins are multifunctional adaptor proteins involved in developmental signaling pathways. One isoform, β-arrestin2 (βarr2), has been implicated in initiation and progression of chronic myeloid leukemia, another myeloproliferative neoplasm closely related to primary myelofibrosis. Accordingly, we investigated the relationship between βarr2 and primary myelofibrosis. In a murine model of MPLW515L-mutant primary myelofibrosis, mice transplanted with donor βarr2-knockout (βarr2-/-) hematopoietic stem cells infected with MPL-mutant retrovirus did not develop myelofibrosis, whereas controls uniformly succumbed to disease. Although transplanted βarr2-/- cells homed properly to marrow, they did not repopulate long-term due to increased apoptosis and decreased self-renewal of βarr2-/- cells. In order to assess the effect of acute loss of βarr2 in established primary myelofibrosis in vivo, we utilized a tamoxifen-induced Cre-conditional βarr2-knockout mouse. Mice that received Cre (+) donor cells and developed myelofibrosis had significantly improved survival compared with controls. These data indicate that lack of antiapoptotic βarr2 mediates marrow failure of murine hematopoietic stem cells overexpressing MPLW515L. They also indicate that βarr2 is necessary for progression of primary myelofibrosis, suggesting that it may serve as a novel therapeutic target in this disease.
β-Arrestin2 mediates progression of murine primary myelofibrosis
Rein, Lindsay A.M.; Wisler, James W.; Kim, Jihee; Theriot, Barbara; Huang, LiYin; Price, Trevor; Yang, Haeyoon; Chen, Wei; Sipkins, Dorothy; Fedoriw, Yuri; Walker, Julia K.L.; Premont, Richard T.; Lefkowitz, Robert J.
2017-01-01
Primary myelofibrosis is a myeloproliferative neoplasm associated with significant morbidity and mortality, for which effective therapies are lacking. β-Arrestins are multifunctional adaptor proteins involved in developmental signaling pathways. One isoform, β-arrestin2 (βarr2), has been implicated in initiation and progression of chronic myeloid leukemia, another myeloproliferative neoplasm closely related to primary myelofibrosis. Accordingly, we investigated the relationship between βarr2 and primary myelofibrosis. In a murine model of MPLW515L-mutant primary myelofibrosis, mice transplanted with donor βarr2-knockout (βarr2–/–) hematopoietic stem cells infected with MPL-mutant retrovirus did not develop myelofibrosis, whereas controls uniformly succumbed to disease. Although transplanted βarr2–/– cells homed properly to marrow, they did not repopulate long-term due to increased apoptosis and decreased self-renewal of βarr2–/– cells. In order to assess the effect of acute loss of βarr2 in established primary myelofibrosis in vivo, we utilized a tamoxifen-induced Cre-conditional βarr2-knockout mouse. Mice that received Cre (+) donor cells and developed myelofibrosis had significantly improved survival compared with controls. These data indicate that lack of antiapoptotic βarr2 mediates marrow failure of murine hematopoietic stem cells overexpressing MPLW515L. They also indicate that βarr2 is necessary for progression of primary myelofibrosis, suggesting that it may serve as a novel therapeutic target in this disease. PMID:29263312
Kapralova, Katarina; Lanikova, Lucie; Lorenzo, Felipe; Song, Jihyun; Horvathova, Monika; Divoky, Vladimir
2014-01-01
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
Kröger, Nicolaus; Panagiota, Victoria; Badbaran, Anita; Zabelina, Tatjana; Triviai, Ioanna; Araujo Cruz, Michelle Maria; Shahswar, Rabia; Ayuk, Francis; Gehlhaar, Marten; Wolschke, Christine; Bollin, Robin; Walter, Carolin; Dugas, Martin; Wiehlmann, Lutz; Lehmann, Ulrich; Koenecke, Christian; Chaturvedi, Anuhar; Alchalby, Haefaa; Stadler, Michael; Eder, Matthias; Christopeit, Max; Göhring, Gudrun; Koenigsmann, Michael; Schlegelberger, Brigitte; Kreipe, Hans-Heinrich; Ganser, Arnold; Stocking, Carol; Fehse, Boris; Thol, Felicitas; Heuser, Michael
2017-07-01
Molecular genetics may influence outcome for patients with myelofibrosis. To determine the impact of molecular genetics on outcome after allogeneic stem cell transplantation, we screened 169 patients with primary myelofibrosis (n = 110), post-essential thrombocythemia/polycythemia vera myelofibrosis (n = 46), and myelofibrosis in transformation (n = 13) for mutations in 16 frequently mutated genes. The most frequent mutation was JAK2V617F (n = 101), followed by ASXL1 (n = 49), calreticulin (n = 34), SRSF2 (n = 16), TET2 (n = 10), U2AF1 (n = 11), EZH2 (n = 7), MPL (n = 6), IDH2 (n = 5), IDH1 (n = 4), and CBL (n = 1). The cumulative incidence of nonrelapse mortality (NRM) at 1 year was 21% and of relapse at 5 years 25%. The 5-year rates progression-free (PFS) and overall survival (OS) were and 56%, respectively. In a multivariate analysis CALR mutation was an independent factor for lower NRM (HR, .415; P = .05), improved PFS (HR, .393; P = .01), and OS (HR, .448; P = .03). ASXL1 and IDH2 mutations were independent risk factors for lower PFS (HR, 1.53 [P = .008], and HR, 5.451 [P = .002], respectively), whereas no impact was observed for "triple negative" patients. Molecular genetics, especially CALR, IDH2, and ASXL1 mutations, may thus be useful to predict outcome independently from known clinical risk factors after allogeneic stem cell transplantation for myelofibrosis. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
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. Copyright© Ferrata Storti Foundation.
Hematopoietic stem cell transplantation for myelofibrosis: where are we now?
Fleischman, Angela G; Maziarz, Richard T
2013-03-01
A succinct yet comprehensive review of the biology of myeloproliferative neoplasms and therapeutic options with a focus on rational decision making for hematopoietic stem cell transplantation. The introduction of Janus kinase inhibitors for myelofibrosis have ushered in a new era for treatment of constitutional symptoms and splenomegaly in myelofibrosis, but the effect of these agents on the natural history of the disease has yet to be clearly defined. Reduced intensity transplants have emerged as the preferred option with recent evidence suggesting fludarabine and melphalan as the optimal conditioning regimen. Myelofibrosis is a rare hematologic malignancy with limited curative therapeutic options. Significant advances in our understanding of disease pathogenesis have led to new targets and new therapeutic options are forthcoming. Hematopoietic stem cell transplantation is at present the only treatment with curative intent; however, the selection of patients who are likely to be best served by this procedure is difficult. As myelofibrosis is an extremely rare disease, randomized clinical trials specifically investigating the role of transplantation in myelofibrosis are unlikely to occur, thus current decision making processes are best guided by retrospective analyses from registry databases and single institution experiences.
Paquette, R L; Meshkinpour, A; Rosen, P J
1994-05-01
Autoimmune myelofibrosis is an uncommon disorder in which patients present with anemia and thrombocytopenia in conjunction with limited clinical manifestations of autoimmune disease or an exacerbation of previously established SLE. The presence of leukoerythroblastosis in a patient with SLE may suggest the presence of myelofibrosis. Conversely, the absence of splenomegaly in a patient with presumed idiopathic myelofibrosis may suggest an autoimmune etiology. Patients with autoimmune myelofibrosis universally have a positive ANA test and frequently have either elevated anti-DNA titers or a positive LE cell preparation. Because physical manifestations of autoimmune disease may not be evident at presentation, all patients found to have myelofibrosis should have an ANA test. Peripheral blood cytopenias in autoimmune myelofibrosis frequently respond to glucocorticoids but regression of bone marrow fibrosis may be incomplete. Hematologic response to treatment parallels that of the associated autoimmune disease.
Myelofibrosis and acquired hemophilia A: a case report.
Wrobel, Marie; Comio, Emilie; Gay, Valerie; Baroudi, Noureddine; Meyer, Pascal; Chuniaud-Louche, Christine; Hacini, Maya; Pica, Gian Matteo
2016-05-07
Myelofibrosis and acquired hemophilia A is a rare association. To the best of our knowledge only one case of myelofibrosis and acquired hemophilia A has been previously described. A 66-year-old Caucasian man diagnosed with myelofibrosis evolving in acute myeloid leukemia was referred to us for postoperative bleeding. Hemostatic studies showed prolonged activated partial thromboplastin time, decreased factor VIII coagulation, and a high factor VIII inhibitor titer; these findings led to a diagnosis of acquired hemophilia A for which he was treated with methylprednisolone and recombinant activated factor VII on admission. Due to a lack of response he was subsequently treated with rituximab combined with activated prothrombin complex concentrates. Furthermore, he received azacytidine to treat the underlying hematological malignancies. Immunosuppressive rituximab therapy resolved acquired hemophilia A with marked efficacy. Rapid and accurate diagnosis, effective hemostatic therapy, and timely treatment for underlying disease are important in the management of acquired hemophilia A secondary to hematological malignancy.
Palta, Anshu; Garg, Shailja; Chauhan, Sandeep; Varma, Neelam
2011-03-01
Coexistence of chronic lymphocytic leukemia (CLL) with myelofibrosis is a rare association with only isolated case reports in the literature. We report an unusual case of CLL in which the cause of anemia was coexistent myelofibrosis. In a case of CLL presenting with refractory anemia, besides common causes like autoimmune hemolytic anemia and marrow infiltration, other causes like myelofibrosis should be searched for.
dos Santos, Leonardo Caires; Ribeiro, Juliana Corrêa da Costa; Silva, Neusa Pereira; Cerutti, Janete; da Silva, Maria Regina Regis; Chauffaille, Maria de Lourdes Lopes Ferrari
2011-01-01
Background The detection of molecular and cytogenetic alterations is important for the diagnosis, prognosis and classification of myeloproliferative neoplasms. Objectives The aim of this study was to detect the following mutations: JAK2 V617F, JAK2 exon 12 and MPL W515K/L, besides chromosomal abnormalities. Furthermore, molecular and cytogenetic alterations were correlated with the leukocyte and platelet counts, hemoglobin levels and age in all patients and with the degree of fibrosis in primary myelofibrosis cases. Methods Twenty cases of polycythemia vera, 17 of essential thrombocythemia and 21 of primary myelofibrosis were selected in the Hematology Department of the Universidade Federal de São Paulo (UNIFESP) between February 2008 and December 2009. The JAK2 V617F, JAK2 exon 12 mutations, MPL W515K and MPL W515L mutations were investigated by real-time PCR and direct sequencing. G-band karyotyping and fluorescence in situ hybridization were used to detect chromosomal abnormalities. Results Chromosomal abnormalities were observed only in polycythemia vera (11.8%) and primary myelofibrosis cases (17.6%), without correlation to clinical data. Chromosomal abnormalities were not detected by fluorescence in situ hybridization. The JAK2 V617F mutation was observed in polycythemia vera (90%), primary myelofibrosis (42.8%) and essential thrombocythemia (47%). Patients with JAK2 V617F-negative polycythemia vera had lower platelet and leukocyte counts compared to V617F-positive polycythemia vera (p-value = 0.0001 and p-value = 0.023, respectively). JAK2 V617F-positive and MPL W515L-positive primary myelofibrosis cases had a higher degree of fibrosis than V617F-negative cases (p-value = 0.022). JAK2 exon 12 mutations were not detected in polycythemia vera patients. The MPL W515L mutation was observed in one case of primary myelofibrosis and in one of essential thrombocythemia. The MPL W515K mutation was not found in patients with essential thrombocythemia or primary
Dos Santos, Leonardo Caires; Ribeiro, Juliana Corrêa da Costa; Silva, Neusa Pereira; Cerutti, Janete; da Silva, Maria Regina Regis; Chauffaille, Maria de Lourdes Lopes Ferrari
2011-01-01
The detection of molecular and cytogenetic alterations is important for the diagnosis, prognosis and classification of myeloproliferative neoplasms. THE AIM OF THIS STUDY WAS TO DETECT THE FOLLOWING MUTATIONS: JAK2 V617F, JAK2 exon 12 and MPL W515K/L, besides chromosomal abnormalities. Furthermore, molecular and cytogenetic alterations were correlated with the leukocyte and platelet counts, hemoglobin levels and age in all patients and with the degree of fibrosis in primary myelofibrosis cases. Twenty cases of polycythemia vera, 17 of essential thrombocythemia and 21 of primary myelofibrosis were selected in the Hematology Department of the Universidade Federal de São Paulo (UNIFESP) between February 2008 and December 2009. The JAK2 V617F, JAK2 exon 12 mutations, MPL W515K and MPL W515L mutations were investigated by real-time PCR and direct sequencing. G-band karyotyping and fluorescence in situ hybridization were used to detect chromosomal abnormalities. Chromosomal abnormalities were observed only in polycythemia vera (11.8%) and primary myelofibrosis cases (17.6%), without correlation to clinical data. Chromosomal abnormalities were not detected by fluorescence in situ hybridization. The JAK2 V617F mutation was observed in polycythemia vera (90%), primary myelofibrosis (42.8%) and essential thrombocythemia (47%). Patients with JAK2 V617F-negative polycythemia vera had lower platelet and leukocyte counts compared to V617F-positive polycythemia vera (p-value = 0.0001 and p-value = 0.023, respectively). JAK2 V617F-positive and MPL W515L-positive primary myelofibrosis cases had a higher degree of fibrosis than V617F-negative cases (p-value = 0.022). JAK2 exon 12 mutations were not detected in polycythemia vera patients. The MPL W515L mutation was observed in one case of primary myelofibrosis and in one of essential thrombocythemia. The MPL W515K mutation was not found in patients with essential thrombocythemia or primary myelofibrosis. The MPL W515L
Sharma, Prashant; Pati, Hara Prasad; Mishra, Pravas Chandra; Dinda, Amit Kumar; Gupta, Ruchika; Sharma, Alok; Jacob, Tony George
2011-08-01
To explore the utility of bone marrow (BM) angiogenesis in differentiating primary myelofibrosis (PMF) from secondary myelofibrosis (MF). CD34 immunostaining was performed on BM biopsies from 21 PMFs, 23 non-PMF myeloproliferative neoplasms (MPN) with associated MF, 20 secondary MF samples, and 10 nonfibrotic controls. Microvessel density (MVD) and microvessel surface area (MSA), along with blood and BM findings were compared between the groups. The post-MPN MF cases included chronic myeloid leukemia-MF and polycythemia vera-MF. Etiologies of secondary MF were metastatic carcinomas, non-MPN hematologic malignancies, tuberculosis, autoimmune MF, and osteopetrosis. Megakaryocytic clustering was the most frequent and intrasinusoidal hematopoiesis the most specific feature of PMF. Higher reticulin grade, collagenization, and osteomyelosclerosis were commoner in PMF. MVD and MSA were significantly increased in fibrotic marrows regardless of etiology. Although mean MVD as well as MSA were highest in PMF, extensive overlaps among groups and marked heterogeneity in the secondary MF group rendered them of limited utility in the differential diagnosis. Enhanced angiogenesis is not entirely specific for PMF. Overlaps with secondary MF limits its differential diagnostic utility. Pathogenetically, our findings suggest that enhanced angiogenesis is a secondary paraneoplastic stromal response shared by various unrelated conditions.
DeLario, Melissa R; Sheehan, Andrea M; Ataya, Ramona; Bertuch, Alison A; Vega, Carlos; Webb, C Renee; Lopez-Terrada, Dolores; Venkateswaran, Lakshmi
2012-05-01
Primary myelofibrosis is a chronic myeloproliferative neoplasm characterized by cytopenias, leukoerythroblastosis, extramedullary hematopoiesis, hepatosplenomegaly and bone marrow fibrosis. Primary myelofibrosis is a rare disorder in adults; children are even less commonly affected by this entity, with the largest pediatric case series reporting on three patients. Most literature suggests spontaneous resolution of myelofibrosis without long term complications in the majority of affected children. We describe the clinical, pathologic, and molecular characteristics and outcomes of nineteen children with primary myelofibrosis treated in our center from 1984 to 2011. Most patients had cytopenia significant enough to require supportive therapy. No child developed malignant transformation and only five of the 19 children (26%) had spontaneous resolution of disease. Sequence analyses for JAK2V617F and MPLW515L mutations were performed on bone marrow samples from 17 and six patients, respectively, and the results were negative. In conclusion, analysis of this large series of pediatric patients with primary myelofibrosis demonstrates distinct clinical, hematologic, bone marrow, and molecular features from adult patients. Copyright © 2012 Wiley Periodicals, Inc.
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
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
2016-06-24
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/.
2018-01-31
Anemia; ASXL1 Gene Mutation; EZH2 Gene Mutation; IDH1 Gene Mutation; IDH2 Gene Mutation; Plasma Cell Myeloma; Primary Myelofibrosis; Recurrent Plasma Cell Myeloma; Secondary Myelofibrosis; Thrombocytopenia
How we treat myelofibrosis after failure of JAK inhibitors.
Pardanani, Animesh; Tefferi, Ayalew
2018-06-04
The introduction of JAK inhibitors, leading to regulatory approval of ruxolitinib, represents a major therapeutic advance in myelofibrosis. Most patients experience reduction in splenomegaly and improved quality of life from symptom improvement. It is a paradox however that, despite inhibition of signaling downstream of disease-related driver mutations, JAK inhibitor treatment is not associated with consistent molecular or pathologic responses in myelofibrosis. Furthermore, there are important limitations to JAK inhibitor therapy including development of dose-limiting cytopenias and/or non-hematological toxicities such as neuropathy or opportunistic infections. Over half the patients discontinue treatment within three years of starting treatment. While data are sparse, clinical outcome after JAK inhibitor 'failure' is likely poor; consequently, it is important to understand patterns of failure to select appropriate salvage treatment(s). An algorithmic approach, particularly one that incorporates cytogenetics/molecular data, is most helpful in selecting stem cell transplant candidates. Treatment of transplant-ineligible patients relies on a problem-based approach that includes use of investigational drugs, or consideration of splenectomy or radiotherapy. Data from early-phase ruxolitinib combination studies, despite promising pre-clinical data, has not shown clear benefit over monotherapy thus far. Development of effective treatment strategies for myelofibrosis patients failing JAK inhibitors remains a major unmet need. Copyright © 2018 American Society of Hematology.
Treatment and management of myelofibrosis in the era of JAK inhibitors
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
Treatment and management of myelofibrosis in the era of JAK inhibitors.
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.
Myelofibrosis associated with prominent periosteal bone apposition. Report of two cases.
Yu, J S; Greenway, G; Resnick, D
1994-01-01
Myelofibrosis is a myeloproliferative disorder that is characterized by splenomegaly and bone marrow replacement by fibrous tissue. The predominant radiographic feature is osteosclerosis; however, in rare instances, periosteal bone apposition or periostitis is apparent in the metaphysis of the distal femura and proximal tibiae. It has been suggested that periostitis, when associated with fever and bone pain, is indicative of more aggressive disease. We report this unusual radiographic finding and its similar appearance to hypertrophic osteoarthropathy in two patients with myelofibrosis. In our patients, the presence of periosteal bone apposition did not correlate with increased disease aggressiveness.
PEG-rHuMGDF ameliorates thrombocytopenia in carboplatin-treated rats without inducing myelofibrosis.
Ide, Y; Harada, K; Imai, A; Yanagida, M
1999-08-01
We examined the effects of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) on carboplatin-induced thrombocytopenia in rats. The focus was on whether myelofibrosis is associated with the PEG-rHuMGDF treatment in this chemotherapy model. After a single injection of carboplatin, rats received subcutaneous PEG-rHuMGDF at pharmacologic doses (1,3, or 30 micrograms/kg) or a vehicle daily for 7 days. PEG-rHuMGDF at more than 3 micrograms/kg ameliorated the thrombocytopenia at day 10. Histologically, no myelofibrosis was detected in the rats treated with PEG-rHuMGDF or vehicle. Subsequently, PEG-rHuMGDF at a suprapharmacologic dose (100 micrograms/kg) was subcutaneously administered to normal and to carboplatin-treated rats daily for 7 days. Histological analysis revealed that the treatment with PEG-rHuMGDF induced myelofibrosis in the normal rats but not in the carboplatin-treated rats. Additionally, the transforming growth factor-beta 1 (TGF-beta 1) levels in the extracellular fluid and the whole extract of the bone marrow were increased to a much lesser degree in the carboplatin-treated rats compared to the normal rats. These findings suggest that PEG-rHuMGDF is effective for carboplatin-induced thrombocytopenia. Proper control of platelet counts and TGF-beta 1 levels is essential so that myelofibrosis is not induced in clinical use.
High Frequency of Copy-Neutral Loss of Heterozygosity in Patients with Myelofibrosis.
Rego de Paula Junior, Milton; Nonino, Alexandre; Minuncio Nascimento, Juliana; Bonadio, Raphael S; Pic-Taylor, Aline; de Oliveira, Silviene F; Wellerson Pereira, Rinaldo; do Couto Mascarenhas, Cintia; Forte Mazzeu, Juliana
2018-01-01
Myelofibrosis is the rarest and most severe type of Philadelphia-negative classical myeloproliferative neoplasms. Although mutually exclusive driver mutations in JAK2, MPL, or CALR that activate JAK-STAT pathway have been related to the pathogenesis of the disease, chromosome abnormalities have also been associated with the phenotype and prognosis of the disease. Here, we report the use of a chromosomal microarray platform consisting of both oligo and SNP probes to improve the detection of chromosome abnormalities in patients with myelofibrosis. Sixteen patients with myelofibrosis were tested, and the results were compared to karyotype analysis. Driver mutations in JAK2, MPL, or CALR were investigated by PCR and MLPA. Conventional cytogenetics revealed chromosome abnormalities in 3 out of 16 cases (18.7%), while chromosomal microarray analysis detected copy-number variations (CNV) or copy-neutral loss of heterozygosity (CN-LOH) alterations in 11 out of 16 (68.7%) patients. These included 43 CN-LOH, 14 deletions, 1 trisomy, and 1 duplication. Ten patients showed multiple chromosomal abnormalities, varying from 2 to 13 CNVs or CN-LOHs. Mutational status for JAK2, CALR, and MPL by MLPA revealed a total of 3/16 (18.7%) patients positive for the JAK2 V617F mutation, 9 with CALR deletion or insertion and 1 positive for MPL mutation. Considering that most of the CNVs identified were smaller than the karyotype resolution and the high frequency of CN-LOHs in our study, we propose that chromosomal microarray platforms that combine oligos and SNP should be used as a first-tier genetic test in patients with myelofibrosis. © 2018 S. Karger AG, Basel.
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
2015-01-01
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
Radioimmunoassay of erythropoietin: circulating levels in normal and polycythemic human beings
DOE Office of Scientific and Technical Information (OSTI.GOV)
Garcia, J.F.; Ebbe, S.N.; Hollander, L.
1982-05-01
Techniques are described in detail for the RIA of human Ep in unextracted plasma or serum. With 100 ..mu..l of sample, the assay 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 showmore » a parallel relationship with the standard reference preparation for Ep. Validation of the RIA is further confirmed by observations of appropriate increases or decreases of circulating Ep levels in physiological and clinical conditions known to be associated with stimulation or 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 RA in the hematology clinic, which will most certainly be expanded with its more extensive use.« less
Oritani, Kenji; Okamoto, Shinichiro; Tauchi, Tetsuzo; Saito, Shigeki; Ohishi, Kohshi; Handa, Hiroshi; Takenaka, Katsuto; Gopalakrishna, Prashanth; Amagasaki, Taro; Ito, Kazuo; Akashi, Koichi
2015-03-01
Ruxolitinib is a potent Janus kinase (JAK) 1/JAK2 inhibitor that has demonstrated rapid and durable improvements in splenomegaly and symptoms and a survival benefit in 2 phase 3 trials in patients with myelofibrosis. Ruxolitinib was well tolerated and effectively reduced splenomegaly and symptom burden in Asian patients with myelofibrosis in the Asian multinational, phase 2 Study A2202. We present a subset analysis of Japanese patients (n = 30) in Study A2202. At data cutoff, 22 patients were ongoing; 8 discontinued, mainly due to adverse events (n = 4). At week 24, 33 % of patients achieved ≥35 % reduction from baseline in spleen volume; 56.0 % achieved ≥50 % reduction from baseline in total symptom score, as measured by the 7-day Myelofibrosis Symptom Assessment Form v2.0. The most common adverse events were anemia (63 %), thrombocytopenia (40 %), nasopharyngitis (37 %), decreased platelet counts (30 %), and diarrhea (30 %). Dose reductions or interruptions due to hemoglobin decreases were more frequent in Japanese patients; no loss of efficacy and no discontinuations due to hematologic abnormalities were observed. Ruxolitinib was well tolerated in Japanese patients and provided substantial reductions in splenomegaly and myelofibrosis-related symptoms similar to those observed in the overall Asian population and phase 3 COMFORT studies.
Efficacy and Safety of Ruxolitinib in the Treatment of Patients with Myelofibrosis
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
Gonzalez, Maria M; Kidd, Laura; Quesada, Jorge; Nguyen, Nghia; Chen, Lei
2013-01-01
Multiple myeloma (MM) is a plasma cell neoplasm involving the bone marrow with organ damage and/or a monoclonal protein (M-spike in the serum and/or urine). This neoplasm typically affects adults over the age of 50. Acute lymphoblastic leukemia (ALL) is a hematological disorder involving at least 20% lymphoblasts in the bone marrow of the B-cell lineage. Acute lymphoblastic leukemia most commonly affects young children with 75% of cases occurring in children less than 6 years old. This case report describes a patient diagnosed with MM in 2000 who achieved a complete remission in 2006 after chemotherapy. Four years later, the patient presented with sudden pancytopenia. A bone marrow biopsy was obtained revealing a B lymphoblastic leukemia in an extensively fibrotic marrow without evidence of MM. A diagnosis of ALL with myelofibrosis is rare in the adult population, acute myelofibrosis (AMF) is more commonly associated with myeloproliferative disorders, and the development of acute leukemia in myeloma is rare. To the best of our knowledge, the presence of MM, ALL, and myelofibrosis in one patient has never been reported.
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
Aggressive B-cell lymphomas in patients with myelofibrosis receiving JAK1/2 inhibitor therapy.
Porpaczy, Edit; Tripolt, Sabrina; Hoelbl-Kovacic, Andrea; Gisslinger, Bettina; Bago-Horvath, Zsuzsanna; Casanova-Hevia, Emilio; Clappier, Emmanuelle; Decker, Thomas; Fajmann, Sabine; Fux, Daniela A; Greiner, Georg; Gueltekin, Sinan; Heller, Gerwin; Herkner, Harald; Hoermann, Gregor; Kiladjian, Jean-Jacques; Kolbe, Thomas; Kornauth, Christoph; Krauth, Maria-Theresa; Kralovics, Robert; Muellauer, Leonhard; Mueller, Mathias; Prchal-Murphy, Michaela; Putz, Eva Maria; Raffoux, Emmanuel; Schiefer, Ana-Iris; Schmetterer, Klaus; Schneckenleithner, Christine; Simonitsch-Klupp, Ingrid; Skrabs, Cathrin; Sperr, Wolfgang R; Staber, Philipp Bernhard; Strobl, Birgit; Valent, Peter; Jaeger, Ulrich; Gisslinger, Heinz; Sexl, Veronika
2018-06-14
Inhibition of Janus-kinase 1/2 (JAK1/2) is a mainstay to treat myeloproliferative neoplasms (MPN). Sporadic observations reported the co-incidence of B-cell non-Hodgkin lymphomas during treatment of MPN with JAK1/2 inhibitors. We assessed 626 MPN patients including 69 with myelofibrosis receiving JAK1/2 inhibitors for lymphoma development. B-cell lymphomas evolved in 4/69 patients (5.8%) upon JAK1/2 inhibition compared to 2/557 (0.36%) with conventional treatment (16-fold increased risk). A similar 15-fold increase was observed in an independent cohort of 929 MPN patients. Considering primary myelofibrosis only (N=216), 3 lymphomas were observed in 31 inhibitor-treated patients (9.7%) versus 1/185 controls (0.54%). Lymphomas were of aggressive B-cell type, extra-nodal or leukemic with high MYC expression in the absence of JAK2 V617F or other MPN-associated mutations. Median time from initiation of inhibitor therapy to lymphoma diagnosis was 25 months. Clonal immunoglobulin gene rearrangements were already detected in the bone marrow during myelofibrosis in 16.3% of patients. Lymphomas occurring during JAK1/2 inhibitor treatment were preceded by a pre-existing B-cell clone in all 3 patients tested. Sequencing verified clonal identity in 2 patients. The effects of JAK1/2 inhibition were mirrored in Stat1 -/- mice: 16/24 mice developed a spontaneous myeloid hyperplasia with the concomitant presence of aberrant B-cells. Transplantations of bone marrow from diseased mice unmasked the outgrowth of a malignant B-cell clone evolving into aggressive B-cell leukemia-lymphoma. We conclude that JAK/STAT1 pathway inhibition in myelofibrosis is associated with an elevated frequency of aggressive B-cell lymphomas. Detection of a pre-existing B-cell clone may identify individuals at risk. Copyright © 2018 American Society of Hematology.
Andrieux, Joris; Roche-Lestienne, Catherine; Geffroy, Sandrine; Desterke, Christophe; Grardel, Nathalie; Plantier, Isabelle; Selleslag, Dominik; Demory, Jean-Loup; Laï, Jean-Luc; Leleu, Xavier; Le Bousse-Kerdiles, Caroline; Vandenberghe, Peter
2007-10-01
In a case with secondary myelofibrosis occurring after essential thrombocythemia, cytogenetic analysis revealed an isolated translocation t(X;17)(q27;q22) in all cells. We found that a bacterial artificial chromosome (BAC) encompassing the breakpoint on chromosome 17 long arm contained only one gene, NOG. We therefore investigated the occurrence of this rare breakpoint in myeloproliferative disorders (MPDs). We identified three more patients with a 17q abnormality in MPDs: myelofibrosis with myeloid metaplasia (MMM); chronic myeloid leukemia positive for t(9;22)(q34;q11) with additional t(4;17)(p15;q22) at diagnosis; and myelofibrosis complicating polycythemia vera. All three cases exhibited a split of BACs containing NOG. The protein encoded by NOG, noggin, acts as an antagonist to bone morphogenetic secreted protein 2 and 4 (BMP2 and BMP4). A comparative analysis of gene expression on Agilent 22K oligonucleotide microarrays in purified CD34+ cells from the blood of MMM patients showed significant downregulation of BMPR2, BMPR1B, BMP2, and BMP8; upregulation of BMP3 and BMP10; and a trend to lower expression of NOG. Thus, given that expression and release of BMPs are important in the induction of osteosclerosis and angiogenic activity, the observed BMP deregulations could be triggered by potential NOG genetic alterations in the four cases here described, and may contribute to the myelofibrotic process characterized by bone marrow stromal reaction including collagen fibrosis, osteosclerosis, and angiogenesis.
The role of the extracellular matrix in primary myelofibrosis
Leiva, O; Ng, S K; Chitalia, S; Balduini, A; Matsuura, S; Ravid, K
2017-01-01
Primary myelofibrosis (PMF) is a myeloproliferative neoplasm that arises from clonal proliferation of hematopoietic stem cells and leads to progressive bone marrow (BM) fibrosis. While cellular mutations involved in the development of PMF have been heavily investigated, noteworthy is the important role the extracellular matrix (ECM) plays in the progression of BM fibrosis. This review surveys ECM proteins contributors of PMF, and highlights how better understanding of the control of the ECM within the BM niche may lead to combined therapeutic options in PMF. PMID:28157219
Sández Montagut, Víctor Manuel; Giráldez Gallego, Álvaro; Ontanilla Clavijo, Guilermo
2018-03-01
We report a case of a regenerative nodular hyperplasia with a portal vein cavernomatosis with a subsequent progression to symptomatic, occlusive thrombosis of the superior mesenteric vein. A thorough investigation resulted in a final diagnosis of primary myelofibrosis associated with the V617F mutation in the JAK2 gene.
DOE Office of Scientific and Technical Information (OSTI.GOV)
Beguin, Y.; Fillet, G.; Bury, J.
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-IIImore » 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.« less
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
2013-10-01
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. Copyright © 2013 Wiley Periodicals, Inc.
Predictive factors for anemia response to erythropoiesis-stimulating agents in myelofibrosis.
Hernández-Boluda, Juan-Carlos; Correa, Juan-Gonzalo; García-Delgado, Regina; Martínez-López, Joaquín; Alvarez-Larrán, Alberto; Fox, María-Laura; García-Gutiérrez, Valentín; Pérez-Encinas, Manuel; Ferrer-Marín, Francisca; Mata-Vázquez, María-Isabel; Raya, José-María; Estrada, Natalia; García, Silvia; Kerguelen, Ana; Durán, María-Antonia; Albors, Manuel; Cervantes, Francisco
2017-04-01
Erythropoiesis-stimulating agents (ESAs) are commonly used to treat the anemia of myelofibrosis (MF), but information on the predictors of response is limited. Results of ESA therapy were analyzed in 163 MF patients with severe anemia, most of whom had inadequate erythropoietin (EPO) levels (<125 U/L) at treatment start. According to the revised criteria of the International Working Group for Myelofibrosis Treatment and Research, anemia response was achieved in 86 patients (53%). Median response duration was 19.3 months. In multivariate analysis, baseline factors associated with a higher response rate were female sex (P=.007), leukocyte count ≥10×10 9 /L (P=.033), and serum ferritin <200 ng/mL (P=.002). Patients with 2 or 3 of the above features had a significantly higher response rate than the remainder (73% vs 28%, respectively; P<.001). Over the 373 patient-years of follow-up on ESA treatment, nine patients developed thrombotic complications (six arterial, three venous), accounting for 2.41 events per 100 patient-years. Survival time from ESA start was longer in anemia responders than in non-responders (P=.011). Besides the already established predictive value of EPO levels, these data can help to identify which MF patients are more likely to benefit from ESA treatment. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Mesenchymal Cell Reprogramming in Experimental MPLW515L Mouse Model of Myelofibrosis.
Han, Ying; Yue, Lanzhu; Wei, Max; Ren, Xiubao; Shao, Zonghong; Zhang, Ling; Levine, Ross L; Epling-Burnette, Pearlie K
2017-01-01
Myelofibrosis is an indicator of poor prognosis in myeloproliferative neoplasms (MPNs), but the precise mechanism(s) contributing to extracellular matrix remodeling and collagen deposition in the bone marrow (BM) niche remains unanswered. In this study, we isolated mesenchymal stromal cells (MSCs) from mice transplanted with wild-type thrombopoietin receptor (MPLWT) and MPLW515L retroviral-transduced bone marrow. Using MSCs derived from MPLW515-transplant recipients, excessive collagen deposition was maintained in the absence of the virus and neoplastic hematopoietic cells suggested that the MSCs were reprogrammed in vivo. TGFβ production by malignant megakaryocytes plays a definitive role promoting myelofibrosis in MPNs. However, TGFβ was equally expressed by MSCs derived from MPLWT and MPLW515L expressing mice and the addition of neutralizing anti-TGFβ antibody only partially reduced collagen secretion in vitro. Interestingly, profibrotic MSCs displayed increased levels of pSmad3 and pSTAT3 suggesting that inflammatory mediators cooperating with the TGFβ-receptor signaling may maintain the aberrant phenotype ex vivo. FGFb is a known suppressor of TGFβ signaling. Reduced collagen deposition by FGFb-treated MSCs derived from MPLW515L mice suggests that the activating pathway is vulnerable to this suppressive mediator. Therefore, our findings have implications for the future investigation of therapies to reverse fibrosis in MPNs.
Mesenchymal Cell Reprogramming in Experimental MPLW515L Mouse Model of Myelofibrosis
Wei, Max; Ren, Xiubao; Shao, Zonghong; Zhang, Ling; Levine, Ross L.; Epling-Burnette, Pearlie K.
2017-01-01
Myelofibrosis is an indicator of poor prognosis in myeloproliferative neoplasms (MPNs), but the precise mechanism(s) contributing to extracellular matrix remodeling and collagen deposition in the bone marrow (BM) niche remains unanswered. In this study, we isolated mesenchymal stromal cells (MSCs) from mice transplanted with wild-type thrombopoietin receptor (MPLWT) and MPLW515L retroviral-transduced bone marrow. Using MSCs derived from MPLW515-transplant recipients, excessive collagen deposition was maintained in the absence of the virus and neoplastic hematopoietic cells suggested that the MSCs were reprogrammed in vivo. TGFβ production by malignant megakaryocytes plays a definitive role promoting myelofibrosis in MPNs. However, TGFβ was equally expressed by MSCs derived from MPLWT and MPLW515L expressing mice and the addition of neutralizing anti-TGFβ antibody only partially reduced collagen secretion in vitro. Interestingly, profibrotic MSCs displayed increased levels of pSmad3 and pSTAT3 suggesting that inflammatory mediators cooperating with the TGFβ-receptor signaling may maintain the aberrant phenotype ex vivo. FGFb is a known suppressor of TGFβ signaling. Reduced collagen deposition by FGFb-treated MSCs derived from MPLW515L mice suggests that the activating pathway is vulnerable to this suppressive mediator. Therefore, our findings have implications for the future investigation of therapies to reverse fibrosis in MPNs. PMID:28135282
Phase II Evaluation of IPI-926, an Oral Hedgehog Inhibitor, in Patients with Myelofibrosis
Sasaki, Koji; Gotlib, Jason R.; Mesa, Ruben A.; Newberry, Kate J.; Ravandi, Farhad; Cortes, Jorge E.; Kelly, Patrick; Kutok, Jeffery L.; Kantarjian, Hagop M.; Verstovsek, Srdan
2016-01-01
The clinical safety and efficacy of IPI-926 was evaluated in 14 patients with myelofibrosis in a phase II study. Patients received 160-mg IPI-926 orally in continuous 28-day cycles. The median treatment duration was 5.1 months, and all patients had discontinued treatment by 7.5 months. Nine patients discontinued due to lack of response as determined by the treating physician, two after developing acute leukemia and one due to disease progression/loss of response. Twelve patients had slight reductions in spleen size (less than 50% from baseline), but symptoms did not improve consistently. One patient achieved transfusion independence lasting 5 months. Reductions in GLI1 mRNA and protein levels, JAK2V617F allele burden, degree of fibrosis, or cytokine levels were observed in some patients, but were not significant when evaluated for the cohort. Low-grade gastrointestinal/liver abnormalities were the most common toxicities. The results did not support continued evaluation of IPI-926 as a monotherapy in myelofibrosis. PMID:25641433
[Myelofibrosis in a benzene-exposed cleaning worker].
Bausà, Roser; Navarro, Lydia; Cortès-Franch, Imma
Long-term exposure to benzene has been associated with several blood malignancies, including aplastic anemia, myeloproliferative neoplasms, and different leukemias. We present a case of primary myelofibrosis in a 59-year-old woman who worked as a cleaner at a car dealership and automobile mechanic shop. For 25 years, she used gasoline as a degreaser and solvent to clean engine parts, floors and work desks on a daily basis. She was referred by her primary care provider to the Occupational Health Unit of Barcelona to assess whether her illness was work-related. Review of her job history and working conditions revealed chronic exposure to benzene in the absence of adequate preventive measures. An association between benzene exposure and myeloproliferative disease was established, suspicious for an occupational disease. Copyright belongs to the Societat Catalana de Salut Laboral.
The role of transforming growth factor-beta in PEG-rHuMGDF-induced reversible myelofibrosis in rats.
Yanagida, M; Ide, Y; Imai, A; Toriyama, M; Aoki, T; Harada, K; Izumi, H; Uzumaki, H; Kusaka, M; Tokiwa, T
1997-12-01
Pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) injected at a suprapharmacologic dose (100 microg/kg) daily for 5 d in normal rats caused marked increases in marrow megakaryocytes and platelet counts at 6-8 d followed by gradual decreases to control levels at 10-20 d. Interestingly, in addition to the expected thrombopoiesis, PEG-rHuMGDF was associated with myelofibrosis with a predominance of reticulin fibres at day 10 followed by complete normalization by day 20. At 6-8 d, the levels of transforming growth factor-beta1 (TGF-beta1) in the extracellular fluid of the marrow, the platelet poor plasma, and the platelet extract were increased 23-, 7- and 2-fold, respectively. The elevated levels of TGF-beta1 were gradually reduced to baseline levels at 13-20 d in accordance with the normalization of myelofibrosis and thrombopoiesis. An ultrastructural analysis showed that large fragments of megakaryocytes were deposited in the marrow parenchyma of PEG-rHuMGDF-treated rats at day 6. PEG-rHuMGDF administration at pharmacologic doses (1 and 10 microg/kg) did not induce the deposition of reticulin fibres in the marrow. These findings suggest that TGF-beta1 leaked from megakaryocytes is involved in the development of the PEG-rHuMGDF-induced myelofibrosis and that this is a reversible process related to the regulation of the excess production of platelets.
Habberstad, Andreas Hanssønn; Tran, Hoa Thi Tuyet; Randen, Ulla; Spetalen, Signe; Dybedal, Ingunn; Tjønnfjord, Geir E; Dahm, Anders Erik Astrup
2018-04-24
Polycythemia vera is a myeloproliferative disease that sometimes evolves to myelofibrosis, causing splenomegaly and neutropenia. In this case report, we describe a patient with polycythemia vera and unexplained neutropenia who later turned out to also have hairy cell leukemia. A middle-aged Caucasian man with polycythemia vera presented to our hospital with chronic mouth ulcers. Later he developed leukopenia and pancytopenia. Bone marrow biopsies showed fibrosis. Further morphological analyses of bone marrow and blood smears revealed probable transformation into acute myeloid leukemia. However, there were also cells indicating hairy cell leukemia. Morphological and immunohistochemical analyses later confirmed the presence of hairy cell leukemia in biopsies that had been present for 3 years. Treatment with cladribine temporarily reversed the patient's neutropenia. Hairy cell leukemia may mimic development to myelofibrosis in patients with polycythemia vera.
Gimenez, Emmanuel; Besses, Carles; Boque, Concepcion; Velez, Patricia; Kerguelen, Ana; Cervantes, Francisco; Ferrer-Marin, Francisca; Perez-Encinas, Manuel; Rodriguez, Mercedes; Gonzalez, Juan Diego; Calzada, Reyes; Hernandez-Boluda, Juan Carlos
2014-06-01
Myelofibrosis is a non-frequent chronic myeloproliferative Philadelphia-negative chromosome neoplasm. It is a heavy incapacitating orphan disease and associated with high morbidity and mortality. In this context, indirect and non-medical costs are expected to be high. The main objective of this project is to estimate the economic burden of this disease in Spain. Thirty-three patients with a diagnosis of myelofibrosis for at least 1 year participated in a questionnaire in three Spanish centers. The study consisted of analyzing in various aspects the cost and impact of the disease; indeed, daily life time limitations with a need of informal care, symtomatology. Additionally, information concerning the clinical management of the disease was collected through a focus group of eight experts. The mean age was 65 years. 15 of 33 patients were at their productive stage. Six had difficulties at work and eight have received informal care. Bone and muscular pain were the main symptoms of patients (72%). The estimated global indirect and non-medical costs of the disease were 86,315€ per patient (20% working and 80% informal care), which reached 104,153€ at productive stage patients (45%) and 168,459€ for more symptomatic patients. The economic burden of indirect and non-medical costs of myelofibrosis are important (15,142€/annual) as a result, and should be considered in economic evaluation, as well as in preventive plans for patients and caregivers, despite the fact that studies with larger numbers of patients should be done.
Splanchnic vein thrombosis as a first manifestation of Primary myelofibrosis
Campos-Cabrera, Gregorio; Campos-Cabrera, Virginia; Campos-Cabrera, Salvador; Campos-Villagómez, José-Luis; Romero-González, Alejandra
2017-01-01
Myeloproliferative neoplasms are chronic disorders of clonal hematopoietic stem cells, characterized by an overproduction of functional granulocytes, red blood cells and / or platelets, and one of the major complications is the occurrence of venous and arterial thrombotic problems caused by increased platelet aggregation and thrombin generation. In this study 11 cases of primary myelofibrosis (PM) were evaluated and 2 debuted with splanchnic venous thrombosis (SVT); so after seeing the results of this study and of world literature, it is suggested that in patients with SVT, diagnostic methods for PM like the JAK2V617F mutation should be included. Copyright: © 2017 SecretarÍa de Salud
Rozovski, Uri; Verstovsek, Srdan; Manshouri, Taghi; Dembitz, Vilma; Bozinovic, Ksenija; Newberry, Kate; Zhang, Ying; Bove, Joseph E; Pierce, Sherry; Kantarjian, Hagop; Estrov, Zeev
2017-01-01
In most patients with primary myelofibrosis, one of three mutually exclusive somatic mutations is detected. In approximately 60% of patients, the Janus kinase 2 gene is mutated, in 20%, the calreticulin gene is mutated, and in 5%, the myeloproliferative leukemia virus gene is mutated. Although patients with mutated calreticulin or myeloproliferative leukemia genes have a favorable outcome, and those with none of these mutations have an unfavorable outcome, prognostication based on mutation status is challenging due to the heterogeneous survival of patients with mutated Janus kinase 2. To develop a prognostic model based on mutation status, we screened primary myelofibrosis patients seen at the MD Anderson Cancer Center, Houston, USA, between 2000 and 2013 for the presence of Janus kinase 2, calreticulin, and myeloproliferative leukemia mutations. Of 344 primary myelofibrosis patients, Janus kinase 2 V617F was detected in 226 (66%), calreticulin mutation in 43 (12%), and myeloproliferative leukemia mutation in 16 (5%); 59 patients (17%) were triple-negatives. A 50% cut-off dichotomized Janus kinase 2-mutated patients into those with high Janus kinase 2 V617F allele burden and favorable survival and those with low Janus kinase 2 V617F allele burden and unfavorable survival. Patients with a favorable mutation status (high Janus kinase 2 V617F allele burden/myeloproliferative leukemia/calreticulin mutation) and aged 65 years or under had a median survival of 126 months. Patients with one risk factor (low Janus kinase 2 V617F allele burden/triple-negative or age >65 years) had an intermediate survival duration, and patients aged over 65 years with an adverse mutation status (low Janus kinase 2 V617F allele burden or triple-negative) had a median survival of only 35 months. Our simple and easily applied age- and mutation status-based scoring system accurately predicted the survival of patients with primary myelofibrosis. Copyright© Ferrata Storti Foundation.
2017-12-01
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
Di Tucci, Anna Angela; Murru, Roberta; Alberti, Daniele; Rabault, Bertrand; Deplano, Simona; Angelucci, Emanuele
2007-01-01
Transfusional iron overload in patients with chronic anemias can result in multiple organ failure. Experience in the management of iron overload in patients with myelodysplastic syndromes is limited, as many do not receive chelation therapy due to short-life expectancy and the difficulties associated with the administration of the current reference standard chelator, deferoxamine. There have, however, been some reports of reduced transfusion requirement associated with chelation therapy in patients with myelodysplastic syndromes and myelofibrosis. Here, we discuss a patient with primary myelofibrosis and related transfusion-dependent anemia who received chelation therapy with the once-daily oral iron chelator, deferasirox. In addition to the reduced iron levels, the patient demonstrated an unexpected reduction in blood transfusion requirement, ultimately resulting in long-lasting transfusion-free survival. PMID:17391307
Sunitinib in Treating Patients With Idiopathic Myelofibrosis
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
Pharmacoeconomics of ruxolitinib therapy in patients with myelofibrosis.
Vandewalle, Björn; Andreozzi, Valeska; Almeida, João; Félix, Jorge
2016-01-01
Overall survival (OS) and other important clinical trial end-points seem increasingly more elusive in supporting rapid and efficient incorporation of innovative cancer drugs in clinical practice. This study proposes a clinical trial based pharmacoeconomic framework to assess the therapeutic and economic value of ruxolitinib in patients with intermediate-2 or high-risk myelofibrosis. Individual patient level 144 week follow-up data from the COMFORT-II trial was used to account for the crossover effect on overall survival. Lifetime treatment benefits and costs were estimated considering detailed patterns of both ruxolitinib dose adjustments and blood transfusion needs. The authors estimate a 3.3 years increment in life expectancy (HR = 0.30; 95% CI = 0.17-0.55; p-value <0.001) and an incremental cost-effectiveness ratio of €40,000 per life year gained with the use of ruxolitinib. This study also demonstrates how valuable information from clinical trials can be used to support informed decisions about the early incorporation of innovative drugs.
Reilly, J T; Snowden, J A; Spearing, R L; Fitzgerald, P M; Jones, N; Watmore, A; Potter, A
1997-07-01
The prognostic significance of cytogenetic abnormalities was determined in 106 patients with well-characterized idiopathic myelofibrosis who were successfully karyotyped at diagnosis. 35% of the cases exhibited a clonal abnormality (37/106), whereas 65% (69/106) had a normal karyotype. Three characteristic defects, namely del(13q) (nine cases), del(20q) (eight cases) and partial trisomy 1q (seven cases), were present in 64.8% (24/37) of patients with clonal abnormalities. Kaplan-Meier plots and log rank analysis demonstrated an abnormal karyotype to be an adverse prognostic variable (P<0.001). Of the eight additional clinical and haematological parameters recorded at diagnosis, age (P<0.01), anaemia (haemoglobin < or = 10 g/dl: P<0.001), platelet (< or = 100 x 10(9)/l, P<0.0001) and leucocyte count (> 10.3 x 10(9)/l; P=0.06) were also associated with a shorter survival. In contrast, sex, spleen and liver size, and percentage blast cells were not found to be significant. Multivariate analysis, using Cox's regression, revealed karyotype, haemoglobin concentration, platelet and leucocyte counts to retain their unfavourable prognostic significance. A simple and useful schema for predicting survival in idiopathic myelofibrosis has been produced by combining age, haemoglobin concentration and karyotype with median survival times varying from 180 months (good-risk group) to 16 months (poor-risk group).
Practical management of patients with myelofibrosis receiving ruxolitinib.
Harrison, Claire; Mesa, Ruben; Ross, David; Mead, Adam; Keohane, Clodagh; Gotlib, Jason; Verstovsek, Srdan
2013-10-01
Myelofibrosis (MF) is characterized by bone marrow fibrosis, progressive anemia and extramedullary hematopoiesis, primarily manifested as splenomegaly. Patients also experience debilitating constitutional symptoms, including sequelae of splenomegaly, night sweats and fatigue. Ruxolitinib (INC424, INCB18424, Jakafi, Jakavi), a JAK1 and JAK2 inhibitor, was approved in November 2011 by the US FDA for the treatment of intermediate- or high-risk MF, and more recently in Europe and Canada for the treatment of MF-related splenomegaly or symptoms. These approvals were based on data from two randomized Phase III studies: COMFORT-I randomized against placebo, and COMFORT-II randomized against best available therapy. In these studies, ruxolitinib rapidly improved multiple disease manifestations of MF, reducing splenomegaly and improving quality of life of patients and potentially prolonging survival. However, as with other chemotherapies, ruxolitinib therapy is associated with some adverse events, such as anemia and thrombocytopenia. The aims of this article are to provide a brief overview of ruxolitinib therapy, to discuss some common adverse events associated with ruxolitinib therapy and to provide clinical management recommendations to maximize patients' benefit from ruxolitinib.
Groepper, Stefanie; Schlue, Jerome; Haferlach, Claudia; Giagounidis, Aristoteles
2016-01-01
Iron overload is a common problem in patients with primary myelofibrosis and anemia due to transfusion dependency. This results in organ damage and toxic effects on hematopoietic cells in the bone marrow. At present, iron chelation therapy is not recommended in patients with myeloproliferative syndromes. We describe a very interesting development in a patient with primary myelofibrosis receiving iron chelation. Transfusion independency and a nearly complete histological remission of the underlying disease occurred within a few weeks of therapy. In addition, a change in molecular genetic findings was observed. Initially a JAK2 and a U2AF1 mutation were detected in the core biopsy. During and after therapy the U2AF1 mutation progressed, whereas the JAK2 mutation could no longer be verified. The improvement in hematopoiesis might results from reduction of oxidative stress on hematopoietic progenitor cells or other unclear deferasirox-mediated effects, whereas the reason for the change in molecular genetic findings is unclear. It appears that deferasirox might have a modulating effect on JAK2-kinase mutations. However, further investigation of selective molecular suppression properties of deferasirox are warranted. © 2016 S. Karger GmbH, Freiburg.
Efficacy of ALK5 inhibition in myelofibrosis
Zhao, Wanke; Ho, Wanting Tina; Han, Ying; Murdun, Cem; Mailloux, Adam W.; Zhang, Ling; Wang, Xuefeng; Budhathoki, Anjali; Pradhan, Kith; Rapaport, Franck; Wang, Huaquan; Shao, Zonghong; Ren, Xiubao; Steidl, Ulrich; Levine, Ross L.; Zhao, Zhizhuang Joe; Verma, Amit; Epling-Burnette, Pearlie K.
2017-01-01
Myelofibrosis (MF) is a bone marrow disorder characterized by clonal myeloproliferation, aberrant cytokine production, extramedullary hematopoiesis, and bone marrow fibrosis. Although somatic mutations in JAK2, MPL, and CALR have been identified in the pathogenesis of these diseases, inhibitors of the Jak2 pathway have not demonstrated efficacy in ameliorating MF in patients. TGF-β family members are profibrotic cytokines and we observed significant TGF-β1 isoform overexpression in a large cohort of primary MF patient samples. Significant overexpression of TGF-β1 was also observed in murine clonal MPLW515L megakaryocytic cells. TGF-β1 stimulated the deposition of excessive collagen by mesenchymal stromal cells (MSCs) by activating the TGF-β receptor I kinase (ALK5)/Smad3 pathway. MSCs derived from MPLW515L mice demonstrated sustained overproduction of both collagen I and collagen III, effects that were abrogated by ALK5 inhibition in vitro and in vivo. Importantly, use of galunisertib, a clinically active ALK5 inhibitor, significantly improved MF in both MPLW515L and JAK2V617F mouse models. These data demonstrate the role of malignant hematopoietic stem cell (HSC)/TGF-β/MSC axis in the pathogenesis of MF, and provide a preclinical rationale for ALK5 blockade as a therapeutic strategy in MF. PMID:28405618
Ungprasert, P; Chowdhary, V R; Davis, M D; Makol, A
2016-04-01
Hematological abnormalities, such as anemia, leucopenia, and thrombocytopenia, secondary to peripheral destruction, are common in systemic lupus erythematosus (SLE). However, cytopenias from autoimmune myelofibrosis (AIMF) are extremely uncommon in SLE, with less than 40 reported cases in the literature. We report the case of a 33-year-old female who presented with bullous skin lesions and pancytopenia as the presenting manifestation of what was ultimately diagnosed as SLE with AIMF. She responded well to glucocorticoids and mycophenolate mofetil. © The Author(s) 2015.
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. © 2016 by The American Society of Hematology.
Mukherjee, Anirban; Bal, Chandrasekhar; Tripathi, Madhavi; Das, Chandan Jyoti; Shamim, Shamim Ahmed
2017-01-01
A 44-year-old female with known primary myelofibrosis presented with shortness of breath. High Resolution Computed Tomography thorax revealed large heterogeneously enhancing extraparenchymal soft tissue density mass involving bilateral lung fields. F-18-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography revealed mildly FDG avid soft tissue density mass with specks of calcification involving bilateral lung fields, liver, and spleen. Subsequent histopathologic evaluation from the right lung mass was suggestive of extramedullary hematopoesis. PMID:28533647
Chronic idiopathic myelofibrosis terminating in extramedullary anaplastic plasmacytoma.
Liu, Min-Ling; Kallakury, Bhaskar; Kessler, Craig; Hartmann, Dan-Paul; Azumi, Norio; Ozdemirli, Metin
2006-02-01
Chronic idiopathic myelofibrosis (CIMF) is a chronic myeloproliferative disorder (CMPD) with progressive fibrosis and extramedullary hematopoiesis. Similar to other CMPDs, the stem cell in CIMF has the potential to differentiate into myeloid or lymphoid lineages, and thus CIMF can culminate in acute leukemia of myeloid or, rarely, lymphoid lineage. We describe an unusual case of CIMF terminating in extramedullary anaplastic plasmacytoma. The patient was a 61-year-old male with an 11-year history of CIMF. His course was complicated by rapidly growing abdominal and inguinal lymphadenopathy. Lymph node biopsy revealed a diffuse undifferentiated infiltrate in the background of extramedullary hematopoiesis. Flow cytometric and immunohistochemical analysis demonstrated plasma cell-related antigens (CD138, CD38, cytoplasmic kappa light chain), epithelial membrane antigen and CD43 in the tumor cells. The myeloid, B-cell or T-cell markers were negative. A clonal immunoglobulin heavy chain gene rearrangement was identified by polymerase chain reaction. The plasma cell origin was further confirmed by electron microscopic examination, which revealed stacks of rough endoplasmic reticulum. Monoclonal gammopathy may occur in CIMF, and rare cases of simultaneous plasma cell myeloma and CIMF have been reported in the literature. However, to the best of our knowledge, this is the first report of CIMF terminating in extramedullary anaplastic plasmacytoma.
Boyd, Elaine M; Bench, Anthony J; Goday-Fernández, Andrea; Anand, Shubha; Vaghela, Krishna J; Beer, Phillip; Scott, Mike A; Bareford, David; Green, Anthony R; Huntly, Brian; Erber, Wendy N
2010-04-01
Approximately 50% of essential thrombocythaemia and primary myelo-fibrosis patients do not have a JAK2 V617F mutation. Up to 5% of these are reported to have a MPL exon 10 mutation but testing for MPL is not routine as there are multiple mutation types. The ability to routinely assess both JAK2 and MPL mutations would be beneficial in the differential diagnosis of unexplained thrombocytosis or myelofibrosis. We developed and applied a high resolution melt (HRM) assay, capable of detecting all known MPL mutations in a single analysis, for the detection of MPL exon 10 mutations. We assessed 175 ET and PMF patients, including 67 that were JAK2 V617F-negative by real time polymerase chain reaction (PCR). Overall, 19/175 (11%) patients had a MPL exon 10 mutation, of whom 16 were JAK2 V617F-negative (16/67; 24%). MPL mutation types were W515L (11), W515K (4), W515R (2) and W515A (1). One patient had both W515L and S505N MPL mutations and these were present in the same haemopoietic colonies. Real time PCR for JAK2 V617F analysis and HRM for MPL exon 10 status identified one or more clonal marker in 71% of patients. This combined genetic approach increases the sensitivity of meeting the World Health Organization diagnostic criteria for these myeloproliferative neoplasms.
Piro, Eugenio; Lentini, Maria; Levato, Luciano; Russo, Antonio; Molica, Stefano
2018-04-25
Iron overload (IOL) due to transfusion-dependent anemia is a serious adverse effect in patients with myelofibrosis (MF). Recent studies have shown that the oral iron chelator deferasirox may prevent multiple organ damage due to IOL in MF. However, it is not clear whether deferasirox may contribute to revert transfusion-dependent anemia. Here, we present a patient with transfusion-dependent intermediate-2 MF according to the International Prognostic Scoring System treated with ruxolitinib in combination with deferasirox. In addition to a reduced serum ferritin level, the patient required less blood transfusions, ultimately resulting in long-lasting transfusion-free survival. © 2018 S. Karger AG, Basel.
Moulard, Odile; Mehta, Jyotsna; Fryzek, Jon; Olivares, Robert; Iqbal, Usman; Mesa, Ruben A
2014-04-01
Primary myelofibrosis (PMF), essential thrombocythemia (ET), and polycythemia vera (PV) are BCR ABL-negative myeloproliferative neoplasms (MPN). Published epidemiology data are scarce, and multiple sources are needed to assess the disease burden. We assembled the most recent information available on the incidence and prevalence of myelofibrosis (MF), ET, and PV by conducting a structured and exhaustive literature review of the published peer-reviewed literature in EMBASE and by reviewing online documentation from disease registries and relevant health registries in European countries. The search was restricted to human studies written in English or French and published between January 1, 2000, and December 6, 2012. Eleven articles identified from EMBASE, three online hematology or oncology registries, and two Web-based databases or reports were used to summarize epidemiological estimates for MF, PV, and ET. The incidence rate of MF ranged from 0.1 per 100,000 per year to 1 per 100,000 per year. Among the various registries, the incidence of PV ranged from 0.4 per 100,000 per year to 2.8 per 100,000 per year, while the literature estimated the range of PV incidence to be 0.68 per 100,000 to 2.6 per 100,000 per year. The estimated incidence of ET was between 0.38 per 100,000 per year and 1.7 per 100,000 per year. While a few studies reported on the MPNs' prevalences, it is difficult to compare them as various types of prevalence were calculated (point prevalence vs. period prevalence) and standardization was made according to different populations (e.g., the world population and the European population). There is a wide variation in both prevalence and incidence estimates observed across European data sources. Carefully designed studies, with standardized definitions of MPNs and complete ascertainment of patients including both primary and secondary MFs, should be conducted so that estimates of the population aimed to receive novel treatments for these neoplasms are
Autoimmune myelofibrosis accompanied by Sjögren's syndrome in a 47, XXX/46, XX mosaic woman.
Takahashi, Tohru
2014-01-01
This report describes a patient with autoimmune myelofibrosis accompanied by Sjögren's syndrome (SS). A 36-year-old woman was admitted due to petechiae, purpura, gingival bleeding, dyspnea on exertion, and a lack of concentration. She had pancytopenia and was diagnosed with SS. A bone marrow study showed hypercellular marrow with reticulin fibrosis. Lymphocytic infiltrates and aggregates composed of a mixture of T and B cells in the marrow were also observed. A chromosomal analysis of the marrow cells showed 47, XXX and an analysis of peripheral lymphocytes revealed 47, XXX/46, XX mosaic results. The patient's cytopenia resolved following treatment with oral prednisolone.
A Review of Ruxolitinib for the Treatment of Myelofibrosis: A Critique of the Evidence.
Wade, Ros; Hodgson, Robert; Biswas, Mousumi; Harden, Melissa; Woolacott, Nerys
2017-02-01
As part of the National Institute for Health and Care Excellence's (NICE) Single Technology Appraisal (STA) process, ruxolitinib was assessed to determine the clinical and cost effectiveness of its use in the treatment of disease-related splenomegaly or symptoms in adults with myelofibrosis. Ruxolitinib had previously been assessed as part of the STA process and was not recommended in NICE guidance issued in June 2013 (TA289). A review of TA289 was commissioned following the availability of new longer-term survival data; a price discount patient access scheme (PAS) was also introduced. The Centre for Reviews and Dissemination (CRD) and Centre for Health Economics (CHE) Technology Appraisal Group at the University of York was commissioned to act as the independent Evidence Review Group (ERG). This article provides a summary of the manufacturer or sponsor of the technology's (referred to as the company) submission, the ERG review and the resulting NICE guidance issued in March 2016. The main clinical effectiveness data were derived from two good-quality multicentre randomised controlled trials (RCTs): COMFORT-II compared ruxolitinib with best available therapy (BAT) and COMFORT-I compared ruxolitinib with placebo. Both RCTs demonstrated a statistically significant reduction in splenomegaly and its associated symptoms in intermediate-2 and high-risk myelofibrosis patients. Overall survival was statistically significantly improved with ruxolitinib compared with BAT at 3.5 years of follow-up in the COMFORT-II trial (hazard ratio 0.58, 95 % CI 0.36-0.93). Grade 3-4 adverse events were more frequent in the ruxolitinib group than in the BAT group; 42 % compared with 25 %. Evidence relating to patients with lower-risk disease or low platelet counts (50-100 × 10 9 /L) was less robust. The company's economic model was well-presented and had an appropriate model structure. The base-case incremental cost-effectiveness ratio (ICER) was estimated to be around £45,000 per
Mesa, Ruben A; Vannucchi, Alessandro M; Mead, Adam; Egyed, Miklos; Szoke, Anita; Suvorov, Aleksandr; Jakucs, Janos; Perkins, Andrew; Prasad, Ritam; Mayer, Jiri; Demeter, Judit; Ganly, Peter; Singer, Jack W; Zhou, Huafeng; Dean, James P; Te Boekhorst, Peter A; Nangalia, Jyoti; Kiladjian, Jean-Jacques; Harrison, Claire N
2017-05-01
Available therapies for myelofibrosis can exacerbate cytopenias and are not indicated for patients with severe thrombocytopenia. Pacritinib, which inhibits both JAK2 and FLT3, induced spleen responses with limited myelosuppression in phase 1/2 trials. We aimed to assess the efficacy and safety of pacritinib versus best available therapy in patients with myelofibrosis irrespective of baseline cytopenias. This international, multicentre, randomised, phase 3 trial (PERSIST-1) was done at 67 sites in 12 countries. Patients with higher-risk myelofibrosis (with no exclusions for baseline anaemia or thrombocytopenia) were randomly assigned (2:1) to receive oral pacritinib 400 mg once daily or best available therapy (BAT) excluding JAK2 inhibitors until disease progression or unacceptable toxicity. Randomisation was stratified by risk category, platelet count, and region. Treatment assignments were known to investigators, site personnel, patients, clinical monitors, and pharmacovigilance personnel. The primary endpoint was spleen volume reduction (SVR) of 35% or more from baseline to week 24 in the intention-to-treat population as assessed by blinded, centrally reviewed MRI or CT. We did safety analyses in all randomised patients who received either treatment. Here we present the final data. This trial is registered with ClinicalTrials.gov, number NCT01773187. Between Jan 8, 2013, and Aug 1, 2014, 327 patients were randomly assigned to pacritinib (n=220) or BAT (n=107). Median follow-up was 23·2 months (IQR 14·8-28·7). At week 24, the primary endpoint of SVR of 35% or more was achieved by 42 (19%) patients in the pacritinib group versus five (5%) patients in the BAT group (p=0·0003). 90 patients in the BAT group crossed over to receive pacritinib at a median of 6·3 months (IQR 5·8-6·7). The most common grade 3-4 adverse events through week 24 were anaemia (n=37 [17%]), thrombocytopenia (n=26 [12%]), and diarrhoea (n=11 [5%]) in the pacritinib group, and anaemia (n
Ironing out the details of iron overload in myelofibrosis: Lessons from myelodysplastic syndromes.
Carreau, Nicole; Tremblay, Douglas; Savona, Michael; Kremyanskaya, Marina; Mascarenhas, John
2016-09-01
Myelofibrosis (MF) and myelodysplastic syndrome (MDS) are hematopoietic stem cell disorders associated with cytopenias and red blood cell (RBC) transfusion dependence. Iron overload (IO) as a consequence of RBC transfusion dependence and its effect on outcomes in MF has not been formally studied. However, IO is a demonstrated poor prognostic feature in patients with MDS and congenital or acquired chronic anemias. Evidence that iron chelation therapy (ICT) reduces the deleterious effects of IO in MDS has led to speculation of benefit in MF. However, data supporting the use of ICT in MF is lacking. Neither disease has clear consensus guidelines for the use of ICT. Moreover, JAK-STAT inhibition, the cornerstone of MF treatment, often contributes to anemia and transfusional requirements. This manuscript reviews known and potential implications of IO in MF and highlights the need for prospective clinical investigations of ICT with consideration in the setting of JAK2 inhibitor therapy. Copyright © 2016 Elsevier Ltd. All rights reserved.
Rumi, Elisa; Boveri, Emanuela; Bellini, Marta; Pietra, Daniela; Ferretti, Virginia V.; Sant’Antonio, Emanuela; Cavalloni, Chiara; Casetti, Ilaria C.; Roncoroni, Elisa; Ciboddo, Michele; Benvenuti, Pietro; Landini, Benedetta; Fugazza, Elena; Troletti, Daniela; Astori, Cesare; Cazzola, Mario
2017-01-01
The recently revised World Health Organization (WHO) classification of myeloid neoplasms recognizes prefibrotic myelofibrosis (prePMF) as a distinct entity, characterized by well-defined histopathologic features together with minor clinical criteria (leukocytes, anemia, increased LDH, splenomegaly). The aim of the study was to examine the clinical relevance of distinguishing prePMF from essential thrombocythemia (ET). We identified in our database all patients affected with ET, prePMF and primary myelofibrosis (PMF) diagnosed according to 2008 WHO criteria with a bone marrow fibrosis grade 0-1 at diagnosis and one DNA sample to define the mutational status. The bone marrow morphology of all 404 identified patients was reviewed by an expert pathologist and patients were reclassified according to the 2016 WHO criteria. After reclassification, our cohort included 269 ET, 109 prePMF, and 26 myeloproliferative neoplasm unclassificable. In comparison with ET, patients with prePMF had higher leukocyte count, lower hemoglobin level, higher platelet count, higher LDH values, and higher number of circulating CD34-positive cells; they showed more frequently splenomegaly (all P values < ·001). CALR mutations were more frequent in prePMF than in ET (35·8% vs 17·8%, P < ·001). PrePMF patients had shorter overall survival (P < ·001) and a trend to a higher incidence of leukemic evolution (P ·067) compared to ET patients, while they did not differ in terms of thrombotic and bleeding complications. In conclusion, ET and prePMF diagnosed according to 2016 WHO criteria are two entities with a different clinical phenotype at diagnosis and a different clinical outcome. PMID:29254200
Palandri, Francesca; Benevolo, Giulia; Iurlo, Alessandra; Abruzzese, Elisabetta; Carella, Angelo M; Paoli, Chiara; Palumbo, Giuseppe A; Bonifacio, Massimiliano; Cilloni, Daniela; Andriani, Alessandro; Guarini, Attilio; Turri, Diamante; Elli, Elena Maria; Falcone, Antonietta; Anaclerico, Barbara; Musto, Pellegrino; Di Renzo, Nicola; Tiribelli, Mario; Zambello, Renato; Spinosa, Caterina; Ricco, Alessandra; Raucci, Letizia; Martino, Bruno; Annunziata, Mario; Pascale, Silvia; Liberati, Anna Marina; La Nasa, Giorgio; Maffioli, Margherita; Breccia, Massimo; Pugliese, Novella; Betti, Silvia; Giglio, Gianfranco; Cappuccio, Antonietta; Reale, Luigi
2018-06-01
Myelofibrosis (MF) is a chronic myeloproliferative neoplasm characterised by an aggressive clinical course, with disabling symptoms and reduced survival. Patients experience a severely impaired quality of life and their families face the upheaval of daily routines and high disease-related financial costs. The aim of this study was to investigate the perceptions of Italian patients and their caregivers about living with MF and the burden of illness associated with MF. A quali-quantitative questionnaire and a prompted written narrative survey were administered to patients affected by primary or post-essential thrombocythemia/post-polycythaemia vera MF and their primary caregiver in 35 Italian haematological centres. In total, 287 questionnaires were returned by patients and 98 by caregivers, with 215 and 62, respectively, including the narrative. At the time of diagnosis, the most commonly expressed emotional states of patients were fear, distress and anger, confirming the difficulty of this phase. A high level of emotional distress was also reported by caregivers. Along the pathway of care, the ability to cope with the disease differed according to the quality of care received. The mean cost to each patient attributable to MF was estimated as €12,466 per year, with an estimated average annual cost of loss of income of €7774 per patient and €4692 per caregiver. Better understanding of the personal life of MF patients and their families could improve the relationships between health workers and patients, resulting in better focused healthcare pathways and more effective financial support to maintain patients in their social roles.
Managing side effects of JAK inhibitors for myelofibrosis in clinical practice.
Saeed, Iram; McLornan, Donal; Harrison, Claire N
2017-07-01
Myelofibrosis (MF) is characterized by bone marrow fibrosis, abnormalities in peripheral counts, extramedullary hematopoiesis, splenomegaly and an increased risk of transformation to acute myeloid leukaemia. The disease course is often heterogeneous and management can range from observation alone through to allogeneic stem cell transplantation. As of 2017, the only approved medication for MF remains the JAK Inhibitor (JAKi), ruxolitinib (Novartis Pharmaceuticals, Basel, Switzerland; Incyte, Wilmington, Detroit, USA) although several others have reached advanced stages of clinical trials. Areas covered: In this review, we focus on the management of both common and uncommon side effects arising from the use of currently approved and clinical trial JAKi. Most of the discussion concerns ruxolitinib although we also cover both pacritinib (CTI BioPharma) and momelotinib (Gilead Sciences, Foster City, California) which have been in recent large, multinational phase III trials. The various approaches to management of JAKi-related side effects are discussed - with particular emphasis to anaemia, thrombocytopaenia and infection risk. Expert commentary: JAK inhibitors are effective in many individuals with MF and have revolutionized the current treatment paradigm. The side effect profile, in the most, is predictable and manageable with high degrees of clinical surveillance and dose modifications.
Tsukamoto, Yasuhiro; Kiyasu, Junichi; Tsuda, Mariko; Ikeda, Motohiko; Shiratsuchi, Motoaki; Ogawa, Yoshihiro; Yufu, Yuji
2018-05-01
A 73-year-old man with primary myelofibrosis (PMF) was being treated with hydroxyurea, which was changed to ruxolitinib treatment because of worsening constitutional symptoms. Although ruxolitinib rapidly induced relief, he developed a high-grade fever. A comprehensive fever work-up found no apparent cause of the fever, except for PMF. Therefore, we increased the dose of ruxolitinib and added prednisolone, which was gradually withdrawn with resolution of the fever. However, the patient subsequently developed disseminated tuberculosis and died eight months after initiation of ruxolitinib. Our case highlights the importance of assessing and monitoring the immune status of patients receiving ruxolitinib.
Marchetti, M; Barosi, G; Cervantes, F; Birgegård, G; Griesshammer, M; Harrison, C; Hehlmann, R; Kiladjian, J-J; Kröger, N; McMullin, M F; Passamonti, F; Vannucchi, A; Barbui, T
2017-04-01
Ruxolitinib is an oral Janus-activated kinase 1 (JAK1)/JAK2 inhibitor approved for the treatment of patients with myelofibrosis based on the results of two randomized clinical trials. However, discordant indications were provided by regulatory agencies and scientific societies for selecting the most appropriate candidates to this drug. The European LeukemiaNet and the Italian Society of Hematology shared the aim of building evidence-based recommendations for the use of ruxolitinib according to the GRADE methodology. Eighteen patient-intervention-comparator-outcome profiles were listed, each of them comparing ruxolitinib to other therapies with the aim of improving one of the three clinical outcomes: (a) splenomegaly, (b) disease-related symptoms, and (c) survival. Ruxolitinib was strongly recommended for improving symptomatic or severe (>15 cm below the costal margin) splenomegaly in patients with an International Prognostic Scoring System (IPSS)/dynamic IPSS risk intermediate 2 or high. Ruxolitinib was also strongly recommended for improving systemic symptoms in patients with an MPN10 score >44, refractory severe itching, unintended weight loss not attributable to other causes or unexplained fever. Because of weak evidence, the panel does not recommend ruxolitinib therapy for improving survival. Also, the recommendations given above do not necessarily apply to patients who are candidates for allogeneic stem cell transplant.
Yacoub, A; Odenike, O; Verstovsek, S
2014-12-01
Considerable clinical experience regarding the long-term efficacy and safety of ruxolitinib has been gathered since the drug was approved in the USA for patients with intermediate or high-risk myelofibrosis (MF) in November 2011. Findings from the pivotal phase 3 COMFORT studies showed that ruxolitinib-associated reductions in MF-related splenomegaly and symptom burden occur rapidly and in the majority of patients. Two- and 3-year follow-up data further suggest that the benefits of ruxolitinib are durable and associated with a survival advantage compared with conventional therapies. However, careful management of treatment-related thrombocytopenia and anemia with dose modifications and supportive care is critical to allow chronic therapy. Based on preliminary evidence, ruxolitinib also allows spleen size and symptom reduction before allogeneic stem cell transplantation without negative effect on engraftment or outcomes. In recent studies, ruxolitinib provided effective management of hematologic parameters and symptoms in patients with polycythemia vera refractory to or intolerant of hydroxyurea.
Ruxolitinib for the management of myelofibrosis: Results of an international physician survey.
Ellis, Martin H; Koren-Michowitz, Maya; Lavi, Noa; Vannucchi, Alessandro M; Mesa, Ruben; Harrison, Claire N
2017-10-01
Ruxolitinib is established as treatment for symptomatic myeloproliferative neoplasm (MPN)-associated myelofibrosis. The strict inclusion and exclusion criteria and dose modification rules that applied to the COMFORTI and II studies that led to the licensing of ruxolitinib are not always applicable to routine clinical practice. Thus physicians now face decisions regarding ruxolitinib use that were not addressed in these pivotal trials. We performed an online survey of hematologists practicing in Europe, Israel, the United Kingdom and the United States. Demographic details regarding the physicians and their practice as relates to MPNs were collected. Management decisions pertaining to the use of ruxolitinib were obtained regarding 10 clinical scenarios relating to anemia, thrombocytopenia, frailty, infection and lack or loss of response to ruxolitnib in MF patients. 140 physicians responded to the survey. There were marked differences regarding their decisions for ruxolitinib administration in MF patients with or developing anemia or thrombocytopenia. Similarly there was little consensus regarding management of patients refractory or losing a response to ruxolitinib. There were differences between "MPN-focused" and "non-MPN-focused" physicians in certain areas. Physician practices regarding management of MF patients experiencing ruxolitinib-related toxicities or in whom response to the drug is lost was variable. This was true of "MPN-focused" and "non-MPN-focused" physicians in certain cases. Physician education and experience in using ruxolitinib may improve patient management. Copyright © 2017 Elsevier Ltd. All rights reserved.
Bien-Willner, Gabriel A; Stankiewicz, Paweł; Lupski, James R; Northup, Jill K; Velagaleti, Gopalrao V N
2005-08-01
Non-allelic homologous recombination (NAHR) between low-copy repeats (LCRs) has been implicated recently in somatic rearrangements including isochromosome i(17q), which is associated with hematologic malignancies as well as solid tumors. In hematological malignancies, the most common i(17q) breakpoint results from LCR-mediated NAHR, which creates a dicentric chromosome, idic(17)(p11.2). We report an elderly patient who presented with primary myelofibrosis (MF) with myeloid metaplasia (MMM), associated with idic(17)(p11.2) as the sole chromosomal abnormality, making this the first idic(17)(p11.2) myeloproliferative case reported in which the breakpoints are mapped to the breakpoint cluster region in proximal 17p. The rearrangement breakpoint maps to the previously defined LCR cluster, further suggesting that the genomic architecture of proximal 17p may be responsible for the formation of the majority of i(17q) cases. We describe our development of a rapid screening test using interphase FISH to detect idic(17)(p11.2), discuss the potential prognostic value of this molecular diagnostic test, and examine the relevance of LCR-mediated NAHR to common rearrangements in neoplasms. Copyright (c) 2005 Wiley-Liss, Inc.
Li, Juan; Prins, Daniel; Park, Hyun Jung; Grinfeld, Jacob; Gonzalez-Arias, Carlos; Loughran, Stephen; Dovey, Oliver M; Klampfl, Thorsten; Bennett, Cavan; Hamilton, Tina L; Pask, Dean C; Sneade, Rachel; Williams, Matthew; Aungier, Juliet; Ghevaert, Cedric; Vassiliou, George S; Kent, David G; Green, Anthony R
2018-02-08
Somatic mutations in the endoplasmic reticulum chaperone calreticulin (CALR) are detected in approximately 40% of patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF). Multiple different mutations have been reported, but all result in a +1-bp frameshift and generate a novel protein C terminus. In this study, we generated a conditional mouse knockin model of the most common CALR mutation, a 52-bp deletion. The mutant novel human C-terminal sequence is integrated into the otherwise intact mouse CALR gene and results in mutant CALR expression under the control of the endogenous mouse locus. CALR del/+ mice develop a transplantable ET-like disease with marked thrombocytosis, which is associated with increased and morphologically abnormal megakaryocytes and increased numbers of phenotypically defined hematopoietic stem cells (HSCs). Homozygous CALR del/del mice developed extreme thrombocytosis accompanied by features of MF, including leukocytosis, reduced hematocrit, splenomegaly, and increased bone marrow reticulin. CALR del/+ HSCs were more proliferative in vitro, but neither CALR del/+ nor CALR del/del displayed a competitive transplantation advantage in primary or secondary recipient mice. These results demonstrate the consequences of heterozygous and homozygous CALR mutations and provide a powerful model for dissecting the pathogenesis of CALR-mutant ET and PMF. © 2018 by The American Society of Hematology.
Masselli, E; Carubbi, C; Gobbi, G; Mirandola, P; Galli, D; Martini, S; Bonomini, S; Crugnola, M; Craviotto, L; Aversa, F; Vitale, M
2015-11-01
Among the three classic Philadelphia chromosome-negative myeloproliferative neoplasms, primary myelofibrosis (PMF) is the most severe in terms of disease biology, survival and quality of life. Abnormalities in the process of differentiation of PMF megakaryocytes (MKs) are a hallmark of the disease. Nevertheless, the molecular events that lead to aberrant megakaryocytopoiesis have yet to be clarified. Protein kinase Cɛ (PKCɛ) is a novel serine/threonine kinase that is overexpressed in a variety of cancers, promoting aggressive phenotype, invasiveness and drug resistance. Our previous findings on the role of PKCɛ in normal (erythroid and megakaryocytic commitment) and malignant (acute myeloid leukemia) hematopoiesis prompted us to investigate whether it could be involved in the pathogenesis of PMF MK-impaired differentiation. We demonstrate that PMF megakaryocytic cultures express higher levels of PKCɛ than healthy donors, which correlate with higher disease burden but not with JAK2V617F mutation. Inhibition of PKCɛ function (by a negative regulator of PKCɛ translocation) or translation (by target small hairpin RNA) leads to reduction in PMF cell growth, restoration of PMF MK differentiation and inhibition of PKCɛ-related anti-apoptotic signaling (Bcl-xL). Our data suggest that targeting PKCɛ directly affects the PMF neoplastic clone and represent a proof-of-concept for PKCɛ inhibition as a novel therapeutic strategy in PMF.
A 7-Gene Signature Depicts the Biochemical Profile of Early Prefibrotic Myelofibrosis
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
Lasho, Terra L; Pardanani, Animesh; McClure, Rebecca F; Mesa, Ruben A; Levine, Ross L; Gilliland, D Gary; Tefferi, Ayalew
2006-12-01
MPLW515L/K and JAK2V617F can co-exist in myelofibrosis with myeloid metaplasia (MMM). The chronology of clonal emergence was studied in three such cases using serially stored bone marrow. At diagnosis, a major MPL515 mutant clone was accompanied by a minor JAK2V617F clone in all three instances. At 25 time points over a period of 4-8 years, allele burden fluctuated but remained high for MPLW515L/K and low for JAK2V617F. We conclude that MPLW515L/K and JAK2V617F are both early events in MMM and allele burden, rather than the mere presence of these mutations, might be relevant to phenotypic variation in myeloproliferative disorders.
Clinical effect of driver mutations of JAK2, CALR, or MPL in primary myelofibrosis.
Rumi, Elisa; Pietra, Daniela; Pascutto, Cristiana; Guglielmelli, Paola; Martínez-Trillos, Alejandra; Casetti, Ilaria; Colomer, Dolors; Pieri, Lisa; Pratcorona, Marta; Rotunno, Giada; Sant'Antonio, Emanuela; Bellini, Marta; Cavalloni, Chiara; Mannarelli, Carmela; Milanesi, Chiara; Boveri, Emanuela; Ferretti, Virginia; Astori, Cesare; Rosti, Vittorio; Cervantes, Francisco; Barosi, Giovanni; Vannucchi, Alessandro M; Cazzola, Mario
2014-08-14
We studied the impact of driver mutations of JAK2, CALR, (calreticulin gene) or MPL on clinical course, leukemic transformation, and survival of patients with primary myelofibrosis (PMF). Of the 617 subjects studied, 399 (64.7%) carried JAK2 (V617F), 140 (22.7%) had a CALR exon 9 indel, 25 (4.0%) carried an MPL (W515) mutation, and 53 (8.6%) had nonmutated JAK2, CALR, and MPL (so-called triple-negative PMF). Patients with CALR mutation had a lower risk of developing anemia, thrombocytopenia, and marked leukocytosis compared with other subtypes. They also had a lower risk of thrombosis compared with patients carrying JAK2 (V617F). At the opposite, triple-negative patients had higher incidence of leukemic transformation compared with either CALR-mutant or JAK2-mutant patients. Median overall survival was 17.7 years in CALR-mutant, 9.2 years in JAK2-mutant, 9.1 years in MPL-mutant, and 3.2 years in triple-negative patients. In multivariate analysis corrected for age, CALR-mutant patients had better overall survival than either JAK2-mutant or triple-negative patients. The impact of genetic lesions on survival was independent of current prognostic scoring systems. These observations indicate that driver mutations define distinct disease entities within PMF. Accounting for them is not only relevant to clinical decision-making, but should also be considered in designing clinical trials. © 2014 by The American Society of Hematology.
Clinical effect of driver mutations of JAK2, CALR, or MPL in primary myelofibrosis
Rumi, Elisa; Pietra, Daniela; Pascutto, Cristiana; Guglielmelli, Paola; Martínez-Trillos, Alejandra; Casetti, Ilaria; Colomer, Dolors; Pieri, Lisa; Pratcorona, Marta; Rotunno, Giada; Sant’Antonio, Emanuela; Bellini, Marta; Cavalloni, Chiara; Mannarelli, Carmela; Milanesi, Chiara; Boveri, Emanuela; Ferretti, Virginia; Astori, Cesare; Rosti, Vittorio; Cervantes, Francisco; Barosi, Giovanni; Vannucchi, Alessandro M.
2014-01-01
We studied the impact of driver mutations of JAK2, CALR, (calreticulin gene) or MPL on clinical course, leukemic transformation, and survival of patients with primary myelofibrosis (PMF). Of the 617 subjects studied, 399 (64.7%) carried JAK2 (V617F), 140 (22.7%) had a CALR exon 9 indel, 25 (4.0%) carried an MPL (W515) mutation, and 53 (8.6%) had nonmutated JAK2, CALR, and MPL (so-called triple-negative PMF). Patients with CALR mutation had a lower risk of developing anemia, thrombocytopenia, and marked leukocytosis compared with other subtypes. They also had a lower risk of thrombosis compared with patients carrying JAK2 (V617F). At the opposite, triple-negative patients had higher incidence of leukemic transformation compared with either CALR-mutant or JAK2-mutant patients. Median overall survival was 17.7 years in CALR-mutant, 9.2 years in JAK2-mutant, 9.1 years in MPL-mutant, and 3.2 years in triple-negative patients. In multivariate analysis corrected for age, CALR-mutant patients had better overall survival than either JAK2-mutant or triple-negative patients. The impact of genetic lesions on survival was independent of current prognostic scoring systems. These observations indicate that driver mutations define distinct disease entities within PMF. Accounting for them is not only relevant to clinical decision-making, but should also be considered in designing clinical trials. PMID:24986690
Tie2 Expressing Monocytes in the Spleen of Patients with Primary Myelofibrosis
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
Rumi, Elisa; Pietra, Daniela; Guglielmelli, Paola; Bordoni, Roberta; Casetti, Ilaria; Milanesi, Chiara; Sant'Antonio, Emanuela; Ferretti, Virginia; Pancrazzi, Alessandro; Rotunno, Giada; Severgnini, Marco; Pietrelli, Alessandro; Astori, Cesare; Fugazza, Elena; Pascutto, Cristiana; Boveri, Emanuela; Passamonti, Francesco; De Bellis, Gianluca; Vannucchi, Alessandro; Cazzola, Mario
2013-05-23
We studied mutations of MPL exon 10 in patients with essential thrombocythemia (ET) or primary myelofibrosis (PMF), first investigating a cohort of 892 consecutive patients. MPL mutation scanning was performed on granulocyte genomic DNA by using a high-resolution melt assay, and the mutant allele burden was evaluated by using deep sequencing. Somatic mutations of MPL, all but one involving codon W515, were detected in 26/661 (4%) patients with ET, 10/187 (5%) with PMF, and 7/44 (16%) patients with post-ET myelofibrosis. Comparison of JAK2 (V617F)-mutated and MPL-mutated patients showed only minor phenotypic differences. In an extended group of 62 MPL-mutated patients, the granulocyte mutant allele burden ranged from 1% to 95% and was significantly higher in patients with PMF or post-ET myelofibrosis compared with those with ET. Patients with higher mutation burdens had evidence of acquired copy-neutral loss of heterozygosity (CN-LOH) of chromosome 1p in granulocytes, consistent with a transition from heterozygosity to homozygosity for the MPL mutation in clonal cells. A significant association was found between MPL-mutant allele burden greater than 50% and marrow fibrosis. These observations suggest that acquired CN-LOH of chromosome 1p involving the MPL location may represent a molecular mechanism of fibrotic transformation in MPL-mutated myeloproliferative neoplasms.
Pietra, Daniela; Guglielmelli, Paola; Bordoni, Roberta; Casetti, Ilaria; Milanesi, Chiara; Sant’Antonio, Emanuela; Ferretti, Virginia; Pancrazzi, Alessandro; Rotunno, Giada; Severgnini, Marco; Pietrelli, Alessandro; Astori, Cesare; Fugazza, Elena; Pascutto, Cristiana; Boveri, Emanuela; Passamonti, Francesco; De Bellis, Gianluca; Vannucchi, Alessandro; Cazzola, Mario
2013-01-01
We studied mutations of MPL exon 10 in patients with essential thrombocythemia (ET) or primary myelofibrosis (PMF), first investigating a cohort of 892 consecutive patients. MPL mutation scanning was performed on granulocyte genomic DNA by using a high-resolution melt assay, and the mutant allele burden was evaluated by using deep sequencing. Somatic mutations of MPL, all but one involving codon W515, were detected in 26/661 (4%) patients with ET, 10/187 (5%) with PMF, and 7/44 (16%) patients with post-ET myelofibrosis. Comparison of JAK2 (V617F)–mutated and MPL-mutated patients showed only minor phenotypic differences. In an extended group of 62 MPL-mutated patients, the granulocyte mutant allele burden ranged from 1% to 95% and was significantly higher in patients with PMF or post-ET myelofibrosis compared with those with ET. Patients with higher mutation burdens had evidence of acquired copy-neutral loss of heterozygosity (CN-LOH) of chromosome 1p in granulocytes, consistent with a transition from heterozygosity to homozygosity for the MPL mutation in clonal cells. A significant association was found between MPL-mutant allele burden greater than 50% and marrow fibrosis. These observations suggest that acquired CN-LOH of chromosome 1p involving the MPL location may represent a molecular mechanism of fibrotic transformation in MPL-mutated myeloproliferative neoplasms. PMID:23575445
Salati, Simona; Zini, Roberta; Nuzzo, Simona; Guglielmelli, Paola; Pennucci, Valentina; Prudente, Zelia; Ruberti, Samantha; Rontauroli, Sebastiano; Norfo, Ruggiero; Bianchi, Elisa; Bogani, Costanza; Rotunno, Giada; Fanelli, Tiziana; Mannarelli, Carmela; Rosti, Vittorio; Salmoiraghi, Silvia; Pietra, Daniela; Ferrari, Sergio; Barosi, Giovanni; Rambaldi, Alessandro; Cazzola, Mario; Bicciato, Silvio; Tagliafico, Enrico; Vannucchi, Alessandro M; Manfredini, Rossella
2016-04-01
Primary myelofibrosis (PMF) is a Myeloproliferative Neoplasm (MPN) characterized by megakaryocyte hyperplasia, progressive bone marrow fibrosis, extramedullary hematopoiesis and transformation to Acute Myeloid Leukemia (AML). A number of phenotypic driver (JAK2, CALR, MPL) and additional subclonal mutations have been described in PMF, pointing to a complex genomic landscape. To discover novel genomic lesions that can contribute to disease phenotype and/or development, gene expression and copy number signals were integrated and several genomic abnormalities leading to a concordant alteration in gene expression levels were identified. In particular, copy number gain in the polyamine oxidase (PAOX) gene locus was accompanied by a coordinated transcriptional up-regulation in PMF patients. PAOX inhibition resulted in rapid cell death of PMF progenitor cells, while sparing normal cells, suggesting that PAOX inhibition could represent a therapeutic strategy to selectively target PMF cells without affecting normal hematopoietic cells' survival. Moreover, copy number loss in the chromatin modifier HMGXB4 gene correlates with a concomitant transcriptional down-regulation in PMF patients. Interestingly, silencing of HMGXB4 induces megakaryocyte differentiation, while inhibiting erythroid development, in human hematopoietic stem/progenitor cells. These results highlight a previously un-reported, yet potentially interesting role of HMGXB4 in the hematopoietic system and suggest that genomic and transcriptional imbalances of HMGXB4 could contribute to the aberrant expansion of the megakaryocytic lineage that characterizes PMF patients. © 2015 UICC.
Florena, A M; Tripodo, C; Di Bernardo, A; Iannitto, E; Guarnotta, C; Porcasi, R; Ingrao, S; Abbadessa, V; Franco, V
2009-04-01
Essential thrombocythaemia (ET) and primary myelofibrosis (PMF) share some clinical and pathological features, but show different biological behaviour and prognosis. The latest contributions to understanding the nature of these disorders have focused on bone marrow microenvironment remodelling and proliferative stress, recognising megakaryocytes (MKCs) as "key-cells". The aim of this study was to investigate the apoptotic profile of ET and PMF MKCs in order to further characterise the biology of these disorders. Bone marrow biopsy samples from 30 patients with ET, and 30 patients with PMF, were immunophenotypically studied for the expression of pro-apoptotic (Fas, Fas-L, Bax, Bad) and anti-apoptotic (Bcl-2, Bcl-XL, hTERT (human telomerase reverse transcriptase)) molecules and the "executioner" molecule caspase-3. The fraction of MKCs undergoing apoptosis was assessed by deoxynucleotidyl transferase-mediated dUTP nick-end labelling. Only the mitochondrial pathway seemed to be involved in MKC apoptosis. The anti-apoptotic molecule Bcl-XL was predominantly found in ET MKCs (50.5% of ET MKCs versus 35% of PMF MKCs; p = 0.036), while pro-apoptotic molecules Bax and Bad showed a prevalent expression in PMF MKCs (30.5% of ET MKCs versus 55% of PMF MKCs; 41% of ET MKCs versus 52% of PMF MKCs; p = 0.001 and p = 0.068, respectively). A significant fraction of PMF MKCs were committed to apoptosis according to caspase-3 expression and TUNEL, while only few ET cells were committed to apoptosis. hTERT was significantly more expressed in PMF (32% of ET MKCs versus 46% of PMF MKCs; p = 0.022), in agreement with the proliferative nature of this disease. It was found that ET and PMF MKCs, which barely differ in terms of morphology and aggregation, are characterised by markedly different apoptotic profiles. The rather high apoptotic fraction of PMF was able to support the fibrotic nature of this process, while the anti-apoptotic profile of ET cells fits well with their "steady
Giraudier, Stéphane; Chagraoui, Hédia; Komura, Emiko; Barnache, Stéphane; Blanchet, Benoit; LeCouedic, Jean Pierre; Smith, David F; Larbret, Frédéric; Taksin, Anne-Laure; Moreau-Gachelin, Françoise; Casadevall, Nicole; Tulliez, Michel; Hulin, Anne; Debili, Najet; Vainchenker, William
2002-10-15
Idiopathic myelofibrosis (IMF) is a chronic myeloproliferative disorder characterized by megakaryocyte hyperplasia and bone marrow fibrosis. Biologically, an autonomous megakaryocyte growth and differentiation is noticed, which contributes to the megakaryocyte accumulation. To better understand the molecular mechanisms involved in this spontaneous growth, we searched for genes differentially expressed between normal megakaryocytes requiring cytokines to grow and IMF spontaneously proliferating megakaryocytes. Using a differential display technique, we found that the immunophilin FKBP51 was 2 to 8 times overexpressed in megakaryocytes derived from patients' CD34(+) cells in comparison to normal megakaryocytes. Overexpression was moderate and confirmed in 8 of 10 patients, both at the mRNA and protein levels. Overexpression of FKBP51 in a UT-7/Mpl cell line and in normal CD34(+) cells induced a resistance to apoptosis mediated by cytokine deprivation with no effect on proliferation. FKBP51 interacts with both calcineurin and heat shock protein (HSP)70/HSP90. However, a mutant FKBP51 deleted in the HSP70/HSP90 binding site kept the antiapoptotic effect, suggesting that the calcineurin pathway was responsible for the FKBP51 effect. Overexpression of FKBP51 in UT-7/Mpl cells induced a marked inhibition of calcineurin activity. Pharmacologic inhibition of calcineurin by cyclosporin A mimicked the effect of FKBP51. The data support the conclusion that FKBP51 inhibits apoptosis through a calcineurin-dependent pathway. In conclusion, FKBP51 is overexpressed in IMF megakaryocytes and this overexpression could be, in part, responsible for the megakaryocytic accumulation observed in this disorder by regulating their apoptotic program.
Alchalby, H; Badbaran, A; Bock, O; Fehse, B; Bacher, U; Zander, A R; Kröger, N
2010-09-01
Monitoring of minimal residual disease (MRD) after allogeneic (allo)-SCT for myelofibrosis (MF) allows recognizing the depth of remission and thus guides application of appropriate therapeutic interventions. MPL W515L/K mutations, which are detected in 5-10% of JAK2V617F-negative patients, may be useful for this purpose. Using a highly sensitive quantitative PCR method, we tested 90 patients with MF who underwent allo-SCT for the presence of MPL W515L/K mutations. Two patients with primary MF were found to harbor MPLW515L while no patient was positive for MPLW515K mutation. Both patients were JAK2V617F negative and cleared the mutation rapidly after allo-SCT and remained negative for a median follow-up of 19 months. The results of molecular monitoring correlated well with other remission parameters such as normalization of peripheral blood counts and morphology and complete donor chimerism. We conclude that MPLW515L can be cleared after allo-SCT and hence may be used as an MRD marker in a proportion of JAK2V617F-negative MF patients.
Engle, E K; Fisher, D A C; Miller, C A; McLellan, M D; Fulton, R S; Moore, D M; Wilson, R K; Ley, T J; Oh, S T
2015-04-01
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.
Moura, L G; Tognon, R; Nunes, N S; Rodrigues, L Cataldi; Ferreira, A F; Kashima, S; Covas, D T; Santana, M; Souto, E X; Perobelli, L; Simões, B P; Dias-Baruffi, M; Castro, F A
2016-10-01
Despite all the knowledge, the cellular and molecular mechanisms involved in myeloproliferative neoplasm (MPN) pathophysiology remain unclear. Authors have shown galectin-1 (Gal-1) and 3 playing roles in tumour angiogenesis and fibrosis, which were correlated with poor prognosis in patients with MPN. In the present study LGALS1 and LGALS3 were differently expressed between polycythemia vera, essential thrombocythemia (ET) and primary myelofibrosis (PMF) diseases. Increased LGALS3 expression was associated with a negative JAK2 V617F status mutation in leucocytes from PMF but not in patients with ET without this mutation. However, a positive Janus kinase 2 (JAK2) V617F cell line established from patients with ET (SET-2 cells) when treated with JAK inhibitor presented high levels of LGALS3. Additionally, high LGALS1 expression was found in CD34(+) cells but not in leucocytes from patients with PMF, in absence of JAK2 V617F mutation, and also in SET-2 cells treated with JAK inhibitor. Thus, our findings indicate that differential expression of LGALS1 and/or LGALS3 in patients with MPN is linked with JAK2 V617F status mutation in these diseases and state of cell differentiation. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
Pardanani, A; Guglielmelli, P; Lasho, T L; Pancrazzi, A; Finke, C M; Vannucchi, A M; Tefferi, A
2011-12-01
MPL and JAK2V617F mutation analysis was performed in 603 patients with primary myelofibrosis (PMF) seen at the Mayo Clinic, USA (n=329) or University of Florence, Italy (n=274). Mutant MPL was detected in 49 (8.1%) patients and JAK2V617F in 350 (58%); 4 patients showed both mutations. MPLW515L/K was the commonest mutation; 2 patients showed novel mutations (L513ins and Q516-P518insAAAA). The US and Italy patient cohorts were separately analyzed for comparison of survival and clinical features between MPL-mutated, JAK2-mutated and JAK2/MPL-unmutated cases. JAK2/MPL-unmutated patients were significantly younger than their JAK2-mutated counterparts, in both patient cohorts (P<0.01). In the Florence only cohort, the presence of mutant MPL was associated with older age (P<0.01) and constitutional symptoms (P=0.04) and JAK2V617F with higher hemoglobin (P<0.01) and leukocyte (P=0.03) count; neither patient cohort showed significant associations with platelet count, hemoglobin <10 g/dl, abnormal/unfavorable karyotype, spleen size or prognostic score distribution. To date, 240 deaths and 79 leukemic transformations have been documented among all 603 study patients. Multivariable analysis disclosed no significant difference in overall or leukemia-free survival between the three molecular subgroups. We conclude that the presence of mutant MPL has narrow and inconsistent phenotypic effect in PMF and does not influence overall or leukemia-free survival.
JAK2 V617F, MPL W515L and JAK2 Exon 12 Mutations in Chinese Patients with Primary Myelofibrosis.
Xia, Jun; Lu, Mi-Ze; Jiang, Yuan-Qiang; Yang, Guo-Hua; Zhuang, Yun; Sun, Hong-Li; Shen, Yun-Feng
2012-03-01
JAK2 V617F, MPL W515L and JAK2 exon 12 mutations are novel acquired mutations that induce constitutive cytokine-independent activation of the JAK-STAT pathway in myeloproliferative disorders (MPD). The discovery of these mutations provides novel mechanism for activation of signal transduction in hematopoietic malignancies. This research was to investigate their prevalence in Chinese patients with primary myelofibrosis (PMF). We introduced allele-specific PCR (AS-PCR) combined with sequence analysis to simultaneously screen JAK2 V617F, MPL W515L and JAK2 exon 12 mutations in 30 patients with PMF. Fifteen PMF patients (50.0%) carried JAK2 V617F mutation, and only two JAK2 V617F-negative patients (6.7%) harbored MPL W515L mutation. None had JAK2 exon 12 mutations. Furthermore, these three mutations were not detected in 50 healthy controls. MPL W515L and JAK2 V617F mutations existed in PMF patients but JAK2 exon 12 mutations not. JAK2 V617F and MPL W515L and mutations might contribute to the primary molecular pathogenesis in patients with PMF.
Alvarez-Larrán, A; Cervantes, F; Bellosillo, B; Giralt, M; Juliá, A; Hernández-Boluda, J C; Bosch, A; Hernández-Nieto, L; Clapés, V; Burgaleta, C; Salvador, C; Arellano-Rodrigo, E; Colomer, D; Besses, C
2007-06-01
The frequency of vascular events and evolution to myelofibrosis (MF) in young individuals with essential thrombocythemia (ET) is not well known. The incidence and predisposing factors to such complications was studied in 126 subjects diagnosed with ET at a median age of 31 years (range: 5-40). Overall survival and probability of survival free of thrombosis, bleeding and MF were analyzed by the Kaplan-Meier method and the presence of the Janus Kinase 2 (JAK2) V617F mutation correlated with the appearance of such complications. The JAK2 mutation (present in 43% of patients) was associated with higher hemoglobin (Hb) (P<0.001) and lower platelets at diagnosis. With a median follow-up of 10 years (range: 4-25), 31 thrombotic events were registered (incidence rate: 2.2 thromboses/100 patients/year). When compared with the general population, young ET patients showed a significant increase in stroke (odds ratio 50, 95% CI: 21.5-115) and venous thromboses (odds ratio 5.3, 95% CI: 3.9-10.6). Thrombosis-free survival was 84% at 10 years, with tobacco use being associated with higher risk of thrombosis. Actuarial freedom from evolution to MF was 97% at 10 years. In conclusion, young ET patients have thrombotic events, especially stroke and venous thrombosis, more frequently than generally considered, whereas they rarely transform to MF.
Erythropoiesis in the aged mouse. I. Response to stimulation in vivo
DOE Office of Scientific and Technical Information (OSTI.GOV)
Udupa, K.B.; Lipschitz, D.A.
1984-04-01
Changes in erythropoiesis with age were studied by examining the hematocrit increase in response to hypoxia in aged mice and by assessing the change in erythropoiesis following the injection of erythropoietin in young and old polycythemic mice. The increase in hematocrit after exposure to hypoxia was more variable and generally lower in old mice than in young mice. When erythropoietin was injected into polycythemic animals, the increase in differentiated erythroid cells and /sup 59/Fe incorporation into erythroid marrow and peripheral blood cells was significantly lower in old mice than in young mice. In contrast to differentiated erythroid cells, there wasmore » less evidence of a reduced response to simulation of the more primitive erythroid progenitor cells of aged animals. The early undifferentiated erythroid progenitor, burst-forming units, did not decrease when either young or aged mice were made polycythemic, and no change following erythropoietin injection was noted. Polycythemia suppressed the late-differentiated erythroid progenitor, erythroid colony-forming units, to a greater extent in aged animals, but when erythropoietin was injected, the percent increase over the subsequent 24 hours was identical to that in young mice. These observations indicate a reduced erythropoietic capacity with age, the abnormality being most obvious in the more mature erythroid precursors.« less
Tefferi, A; Abdel-Wahab, O; Cervantes, F; Crispino, J D; Finazzi, G; Girodon, F; Gisslinger, H; Gotlib, J; Kiladjian, J-J; Levine, R L; Licht, J D; Mullally, A; Odenike, O; Pardanani, A; Silver, R T; Solary, E; Mughal, T
2011-01-01
Immediately following the 2010 annual American Society of Hematology (ASH) meeting, the 5th International Post-ASH Symposium on Chronic Myelogenous Leukemia and BCR-ABL1-Negative Myeloproliferative Neoplasms (MPNs) took place on 7–8 December 2010 in Orlando, Florida, USA. During this meeting, the most recent advances in laboratory research and clinical practice, including those that were presented at the 2010 ASH meeting, were discussed among recognized authorities in the field. The current paper summarizes the proceedings of this meeting in BCR-ABL1-negative MPN. We provide a detailed overview of new mutations with putative epigenetic effects (TET oncogene family member 2 (TET2), additional sex comb-like 1 (ASXL1), isocitrate dehydrogenase (IDH) and enhancer of zeste homolog 2 (EZH2)) and an update on treatment with Janus kinase (JAK) inhibitors, pomalidomide, everolimus, interferon-α, midostaurin and cladribine. In addition, the new ‘Dynamic International Prognostic Scoring System (DIPSS)-plus' prognostic model for primary myelofibrosis (PMF) and the clinical relevance of distinguishing essential thrombocythemia from prefibrotic PMF are discussed. PMID:23471017
Wilkins, Bridget S; Radia, Deepti; Woodley, Claire; Farhi, Sarah El; Keohane, Clodagh; Harrison, Claire N
2013-12-01
Ruxolitinib, a JAK1/JAK2 inhibitor, is currently the only pharmacological agent approved for the treatment of myelofibrosis. Approval was based on findings from two phase 3 trials comparing ruxolitinib with placebo (COMFORT-I) and with best available therapy (COMFORT-II) for the treatment of primary or secondary myelofibrosis. In those pivotal trials, ruxolitinib rapidly improved splenomegaly, disease-related symptoms, and quality of life and prolonged survival compared with both placebo and conventional treatments. However, for reasons that are currently unclear, there were only modest histomorphological changes in the bone marrow, and only a subset of patients had significant reductions in JAK2 V617F clonal burden. Here we describe a patient with post-polycythemia vera myelofibrosis who received ruxolitinib at our institution (Guy's and St. Thomas' NHS Foundation Trust, London, United Kingdom) as part of the COMFORT-II study. While on treatment, the patient had dramatic improvements in splenomegaly and symptoms shortly after starting ruxolitinib. With longer treatment, the patient had marked reductions in JAK2 V617F allele burden, and fibrosis of the bone marrow resolved after approximately 3 years of ruxolitinib treatment. To our knowledge, this is the first detailed case report of resolution of fibrosis with a JAK1/JAK2 inhibitor. ClinicalTrials.gov Identifier: NCT00934544.
Rupoli, Serena; Goteri, Gaia; Picardi, Paola; Micucci, Giorgia; Canafoglia, Lucia; Scortechini, Anna Rita; Federici, Irene; Giantomassi, Federica; Da Lio, Lidia; Zizzi, Antonio; Honorati, Elisa; Leoni, Pietro
2015-04-16
Vascular events represent the most frequent complications of thrombocytemias. We aimed to evaluate their risk in the WHO histologic categories of Essential Thrombocytemia (ET) and early Primary Myelofibrosis (PMF). From our clinical database of 283 thrombocytemic patients, we selected those with available bone marrow histology performed before any treatment, at or within 1 year from diagnosis, and reclassified the 131 cases as true ET or early PMF, with or without fibrosis, according to the WHO histological criteria. Vaso-occlusive events at diagnosis and in the follow-up were compared in the WHO-groups. Histologic review reclassified 61 cases as ET and 72 cases as early PMF (26 prefibrotic and 42 with grade 1 or 2 fibrosis). Compared to ET, early PMF showed a significant higher rate of thrombosis both in the past history (22% vs 8%) and at diagnosis (15.2% vs 1.6%), and an increased leukocyte count (8389 vs 7500/mmc). Venous thromboses (mainly atypical) were relatively more common in PMF than in ET. Patients with prefibrotic PMF, although younger, showed a significant higher 15-year risk of developing thrombosis (48% vs 16% in fibrotic PMF and 17% in ET). At multivariate analysis, age and WHO histology were both independent risk-factors for thrombosis during follow-up; patients >60 yr-old or with prefibrotic PMF showed a significantly higher risk at 20 years than patients <60 yr-old with ET or fibrotic PMF (47% vs 4%, p = 0.005). Our study support the importance of WHO histologic categories in the thrombotic risk stratification of patients with thrombocytemias. The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2020211863144412 .
Wang, Xiaoli; Zhang, Wei; Ishii, Takefumi; Sozer, Selcuk; Wang, Jiapeng; Xu, Mingjiang; Hoffman, Ronald
2011-01-01
The abnormal trafficking of CD34+ cells is a unique characteristic of primary myelofibrosis (PMF). We have further studied the behavior of PMF CD34+ cells by examining their homing to the marrow and the spleens of NOD/SCID mice. Following the infusion of PMF and normal G-CSF mobilized peripheral blood (mPB) CD34+ cells into NOD/SCID mice, reduced numbers of PMF CD34+ cells and CFU-GM as compared to mPB were detected in the marrow of these mice while similar numbers of PMF and mPB CD34+ cells and CFU-GM homed to their spleens. The abnormal homing of PMF CD34+ cells was associated with reduced expression of CXCR4, but was not related to the presence of JAK2V617F. The sequential treatment of PMF CD34+ cell with the chromatin modifying agents, 5-aza-2'-deoxycytidine (5azaD) and trichostatin A (TSA) but not treatment with small molecule inhibitors of JAK2 resulted in the generation of increased numbers of CD34+CXCR4+ cells which was accompanied by enhanced homing of PMF CD34+ cells to the marrow but not the spleens of NOD/SCID mice. Following 5azaD/TSA treatment JAK2V617F negative PMF hematopoietic progenitor cells preferentially homed to the marrow but not the spleens of recipient mice. Our data suggest that PMF CD34+ cells are characterized by a reduced ability to home to the marrow but not the spleens of NOD/SCID mice and that this homing defect can be corrected by sequential treatment with chromatin modifying agents. PMID:19752087
Nienhold, Ronny; Zmajkovic, Jakub; Hao-Shen, Hui; Geier, Florian; Dirnhofer, Stephan; Feenstra, Jelena D. Milosevic
2016-01-01
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
Bozzini, C E; Barceló, A C; Conti, M I; Martínez, M P; Lezón, C E; Bozzini, C; Alippi, R M
1997-02-01
Although a great deal of evidence supports the hypothesis that plasma erythropoietin (EPO) levels of mammals are related to the oxygen supply to the tissues relative to their oxygen needs, several observation millitate against its inherent simplicity. This study presents our results obtained from in vivo experiments that suggest that hypoxia-dependent EPO production can be altered by conditions which apparently do not modify the tissue oxygen supply/demand ratio. Hypoxia-dependent EPO production rate (EPO-PR), derived from plasma EPO titers and plasma EPO half-lives, were estimated in both transfused-polycythemic and normocythemic mouse models subjected to different treatments. From calculations of the O2 carrying capacity of blood and body O2 consumption, it was assumed that the tissue supply/demand ratios were similar in both experimental and control mice of the same model at the time of induction of EPO production. The following observations were worth noting: (1) EPO-PRs in transfused polycythemic mice whose erythropoietic rates were stimulated by intermittent exposure to hypobaria (0.5 atm, 18 hr/day x 3 weeks), phenylhydrazine administration (40 mg/kg at weekly intervals x 3 weeks) or repeated rh-EPO injections (1500 U/kg 3 times a week x 3 weeks) before transfusion were more than five times high than in comparabily polycythemic mice whose erythropoietic rates were not stimulated previously; and (2) EPO-PR in response to hypobaric hypoxia was 2.08 times normal in normocythemic mice with cyclophosphamide (100 mg/kg) induced depression of erythropoiesis, and 0.33 times normal in normocythemic mice with rh-EPO (400 U/kg x 2) induced enhancement of erythropoiesis. Although the results obtained in polycythemic mice are difficult to explain, those from normocythemic mice suggest the existence of a feedback mechanism between EPO-responsive cells and EPO-producing cells. Both demonstrate the existence of experimental conditions in which modulation of the hypoxia
MPLW515L Is a Novel Somatic Activating Mutation in Myelofibrosis with Myeloid Metaplasia
Pikman, Yana; Lee, Benjamin H; Mercher, Thomas; McDowell, Elizabeth; Ebert, Benjamin L; Gozo, Maricel; Cuker, Adam; Wernig, Gerlinde; Moore, Sandra; Galinsky, Ilene; DeAngelo, Daniel J; Clark, Jennifer J; Lee, Stephanie J; Golub, Todd R; Wadleigh, Martha; Gilliland, D. Gary; Levine, Ross L
2006-01-01
Background The JAK2V617F allele has recently been identified in patients with polycythemia vera (PV), essential thrombocytosis (ET), and myelofibrosis with myeloid metaplasia (MF). Subsequent analysis has shown that constitutive activation of the JAK-STAT signal transduction pathway is an important pathogenetic event in these patients, and that enzymatic inhibition of JAK2V617F may be of therapeutic benefit in this context. However, a significant proportion of patients with ET or MF are JAK2V617F-negative. We hypothesized that activation of the JAK-STAT pathway might also occur as a consequence of activating mutations in certain hematopoietic-specific cytokine receptors, including the erythropoietin receptor (EPOR), the thrombopoietin receptor (MPL), or the granulocyte-colony stimulating factor receptor (GCSFR). Methods and Findings DNA sequence analysis of the exons encoding the transmembrane and juxtamembrane domains of EPOR, MPL, and GCSFR, and comparison with germline DNA derived from buccal swabs, identified a somatic activating mutation in the transmembrane domain of MPL (W515L) in 9% (4/45) of JAKV617F-negative MF. Expression of MPLW515L in 32D, UT7, or Ba/F3 cells conferred cytokine-independent growth and thrombopoietin hypersensitivity, and resulted in constitutive phosphorylation of JAK2, STAT3, STAT5, AKT, and ERK. Furthermore, a small molecule JAK kinase inhibitor inhibited MPLW515L-mediated proliferation and JAK-STAT signaling in vitro. In a murine bone marrow transplant assay, expression of MPLW515L, but not wild-type MPL, resulted in a fully penetrant myeloproliferative disorder characterized by marked thrombocytosis (Plt count 1.9–4.0 × 10 12/L), marked splenomegaly due to extramedullary hematopoiesis, and increased reticulin fibrosis. Conclusions Activation of JAK-STAT signaling via MPLW515L is an important pathogenetic event in patients with JAK2V617F-negative MF. The bone marrow transplant model of MPLW515L-mediated myeloproliferative
MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia.
Pikman, Yana; Lee, Benjamin H; Mercher, Thomas; McDowell, Elizabeth; Ebert, Benjamin L; Gozo, Maricel; Cuker, Adam; Wernig, Gerlinde; Moore, Sandra; Galinsky, Ilene; DeAngelo, Daniel J; Clark, Jennifer J; Lee, Stephanie J; Golub, Todd R; Wadleigh, Martha; Gilliland, D Gary; Levine, Ross L
2006-07-01
The JAK2V617F allele has recently been identified in patients with polycythemia vera (PV), essential thrombocytosis (ET), and myelofibrosis with myeloid metaplasia (MF). Subsequent analysis has shown that constitutive activation of the JAK-STAT signal transduction pathway is an important pathogenetic event in these patients, and that enzymatic inhibition of JAK2V617F may be of therapeutic benefit in this context. However, a significant proportion of patients with ET or MF are JAK2V617F-negative. We hypothesized that activation of the JAK-STAT pathway might also occur as a consequence of activating mutations in certain hematopoietic-specific cytokine receptors, including the erythropoietin receptor (EPOR), the thrombopoietin receptor (MPL), or the granulocyte-colony stimulating factor receptor (GCSFR). DNA sequence analysis of the exons encoding the transmembrane and juxtamembrane domains of EPOR, MPL, and GCSFR, and comparison with germline DNA derived from buccal swabs, identified a somatic activating mutation in the transmembrane domain of MPL (W515L) in 9% (4/45) of JAKV617F-negative MF. Expression of MPLW515L in 32D, UT7, or Ba/F3 cells conferred cytokine-independent growth and thrombopoietin hypersensitivity, and resulted in constitutive phosphorylation of JAK2, STAT3, STAT5, AKT, and ERK. Furthermore, a small molecule JAK kinase inhibitor inhibited MPLW515L-mediated proliferation and JAK-STAT signaling in vitro. In a murine bone marrow transplant assay, expression of MPLW515L, but not wild-type MPL, resulted in a fully penetrant myeloproliferative disorder characterized by marked thrombocytosis (Plt count 1.9-4.0 x 10(12)/L), marked splenomegaly due to extramedullary hematopoiesis, and increased reticulin fibrosis. Activation of JAK-STAT signaling via MPLW515L is an important pathogenetic event in patients with JAK2V617F-negative MF. The bone marrow transplant model of MPLW515L-mediated myeloproliferative disorders (MPD) exhibits certain features of human MF
A Phase 1/2 Study To Evaluate ASN002 In Relapsed/Refractory Lymphoma And Advanced Solid Tumors
2018-04-30
Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle-Cell; Lymphoma, Follicular; Cancer; Neoplasm; Tumor; Lymphoma, Malignant; Lymphoma, B-cell; Lymphoma, Non-Hodgkin; B-Cell Chronic Lymphocytic Leukemia; B-Cell Leukemia, Chronic; B-Lymphocytic Leukemia, Chronic; Chronic Lymphocytic Leukemia; Leukemia, Lymphocytic, Chronic; Leukemia, Lymphocytic, Chronic, B Cell; Myelofibrosis; Chronic Idiopathic Myelofibrosis; Idiopathic Myelofibrosis; Lymphoma, T Cell, Peripheral; Peripheral T-Cell Lymphoma; T-Cell Lymphoma, Peripheral
Mide, S M; Huygens, P; Bozzini, C E; Fernandez Pol, J A
2001-01-01
Hemopoietic cells, the extracellular matrix, growth factors and the microenvironment are involved in the regulation of hemopoiesis. Although the regulation of erythropoiesis is well understood at the cellular level in vivo and in vitro, the role of hemopoietic sites of erythroid progenitors production has not been well defined in both steady state conditions and in stress erythropoiesis. In this study we examined the qualitative erythroid differentiation and quantitative changes of the erythroid progenitors in different erythropoietic organs during erythropoiesis of stress in a hypoxia-induced polycythemia and post-hypoxic changes in a mice model. Chronic intermittent exposure to hypobaric hypoxia induced polycythemia in mice and the post-hypoxic period was characterized by total suppression of erythropoiesis. The number and distribution in hemopoietic sites of Immature Erythroid Burst (BFU-EI), Mature Erythroid Burst (BFU-EM) and Erythroid Colony Forming Units (CFU-E) was evaluated in bone marrow and spleen of hypoxic and post-hypoxic mice after removal from the chamber. The number of BFU-EI and CFU-E, was evaluated in both femoral bone marrow and spleen of ex-hypoxic polycythemic mice, at two times intervals after the end of hypoxia. We found that in both bone marrow and spleen, the kinetics of the CFU-E pool was characterized by a sharp fall from above normal to lower than normal levels. BFU-EM increased from normal to higher than normal levels. These results have been correlated with both erythropoietin (EPO) and the erythropoietic activity. The results show that EPO levels largely control both the differentiation and the amplification of the CFU-E pool and they suggest that EPO may acts as a "survival factor" at the CFU-E level and/or increase the flow of cells from BFU-E to CFU-E. After the termination of the period of hypoxia and during post-hypoxia there was a reduction in EPO production which subsequently caused a depletion of the CFU-E population
Mascarenhas, J; Mughal, TI; Verstovsek, S
2012-01-01
Myeloproliferative neoplasms (MPN) are debilitating stem cell-derived clonal myeloid malignancies. Conventional treatments for the BCR-ABL1-negative MPN including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) have, so far, been unsatisfactory. Following the discovery of dysregulated JAK-STAT signaling in patients with MPN, many efforts have been directed toward the development of molecularly targeted therapies, including inhibitors of JAK1 and JAK2. Ruxolitinib (previously known as INCB018424; Incyte Corporation, Wilmington, Delaware, USA) is a rationally designed potent oral JAK1 and JAK2 inhibitor that has undergone clinical trials in patients with PV, ET, and PMF. Ruxolitinib was approved on November 16, 2011 by the United States Food and Drug Administration for the treatment of intermediate or high-risk myelofibrosis (MF), including patients with PMF, post-PV MF, and post-ET MF. In randomized phase III studies, ruxolitinib treatment resulted in significant and durable reductions in splenomegaly and improvements in disease-related symptoms in patients with MF compared with placebo or best available therapy. The most common adverse events were anemia and thrombocytopenia, which were manageable and rarely led to discontinuation. This review addresses the cellular and molecular biology, and the clinical management of MPN. PMID:22830345
Lucijanic, Marko; Livun, Ana; Stoos-Veic, Tajana; Pejsa, Vlatko; Jaksic, Ozren; Cicic, David; Lucijanic, Jelena; Romic, Zeljko; Orehovec, Biserka; Aralica, Gorana; Miletic, Marko; Kusec, Rajko
2018-05-01
To investigate the clinical and prognostic significance of absolute basophil count (ABC) in patients with primary myelofibrosis (PMF). We retrospectively investigated 58 patients with PMF treated in our institution in the period from 2006 to 2017. ABC was obtained in addition to other hematological and clinical parameters. Patients were separated into high and low ABC groups using the Receiver operating characteristic curve analysis. ABC was higher in PMF patients than in healthy controls (P < 0.001). Patients with high ABC had higher white blood cells (P < 0.001), higher red cell distribution width (P = 0.035), higher lactate dehydrogenase (P < 0.001), more frequently had circulatory blasts (P < 0.001), constitutional symptoms (P = 0.030) and massive splenomegaly (P = 0.014). ABC was also positively correlated with absolute monocyte count (AMC) (P < 0.001) and other components of differential blood count. There was no difference in ABC regarding driver mutations or degree of bone marrow fibrosis. Univariately, high ABC was significantly associated with inferior overall survival (hazard ratio (HR) 4.79, P < 0.001). This effect remained statistically significant (HR 4.27, P = 0.009) in a multivariate Cox regression model adjusted for age, gender, Dynamic International Prognostic Scoring System (HR 2.6, P = 0.001) and AMC (HR 8.45, P = 0.002). High ABC reflects higher disease activity and stronger proliferative potential of disease. ABC and AMC independently predict survival and therefore seem to reflect different underlying pathophysiologic processes. Hence, both have a potential for improvement of current prognostic scores. Basophils represent a part of malignant clone in PMF and are associated with unfavorable disease features and poor prognosis which is independent of currently established prognostic scoring system and monocytosis.
... into all of your blood cells. Your blood is made of: Red blood cells (which carry oxygen to your tissues) White blood cells (which fight infection) Platelets (which help your blood clot) When the bone marrow is scarred, it cannot make enough blood cells. Anemia , ...
Seymour, John F.; Roberts, Andrew W.; Wadleigh, Martha; To, L. Bik; Scherber, Robyn; Turba, Elyce; Dorr, Andrew; Zhu, Joy; Wang, Lixia; Granston, Tanya; Campbell, Mary S.; Mesa, Ruben A.
2015-01-01
Pacritinib (SB1518) is a Janus kinase 2 (JAK2), JAK2(V617F), and Fms-like tyrosine kinase 3 inhibitor that does not inhibit JAK1. It demonstrated a favorable safety profile with promising efficacy in phase 1 studies in patients with primary and secondary myelofibrosis (MF). This multicenter phase 2 study further characterized the safety and efficacy of pacritinib in the treatment of patients with MF. Eligible patients had clinical splenomegaly poorly controlled with standard therapies or were newly diagnosed with intermediate- or high-risk Lille score. Patients with any degree of cytopenia were eligible. Thirty-five patients were enrolled. At entry, 40% had hemoglobin <10 g/dL and 43% had platelets <100 000× 109/L. Up to week 24, 8 of 26 evaluable patients (31%) achieved a ≥35% decrease in spleen volume determined by magnetic resonance imaging and 14 of 33 (42%) attained a ≥50% reduction in spleen size by physical examination. Median MF symptom improvement was ≥50% for all symptoms except fatigue. Grade 1 or 2 diarrhea (69%) and nausea (49%) were the most common treatment-emergent adverse events. The study drug was discontinued in 9 patients (26%) due to adverse events (4 severe). Pacritinib is an active agent in patients with MF, offering a potential treatment option for patients with preexisting anemia and thrombocytopenia. This trial was registered at www.clinicaltrials.gov as #NCT00745550. PMID:25762180
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.
2014-01-01
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
[Prognostic value of JAK2, MPL and CALR mutations in Chinese patients with primary myelofibrosis].
Xu, Z F; Li, B; Liu, J Q; Li, Y; Ai, X F; Zhang, P H; Qin, T J; Zhang, Y; Wang, J Y; Xu, J Q; Zhang, H L; Fang, L W; Pan, L J; Hu, N B; Qu, S Q; Xiao, Z J
2016-07-01
To evaluate the prognostic value of JAK2, MPL and CALR mutations in Chinese patients with primary myelofibrosis (PMF). Four hundred and two Chinese patients with PMF were retrospectively analyzed. The Kaplan-Meier method, the Log-rank test, the likelihood ratio test and the Cox proportional hazards regression model were used to evaluate the prognostic scoring system. This cohort of patients included 209 males and 193 females with a median age of 55 years (range: 15- 89). JAK2V617F mutations were detected in 189 subjects (47.0% ), MPLW515 mutations in 13 (3.2%) and CALR mutations in 81 (20.1%) [There were 30 (37.0%) type-1, 48 (59.3%) type-2 and 3 (3.7%) less common CALR mutations], respectively. 119 subjects (29.6%) had no detectable mutation in JAK2, MPL or CALR. Univariate analysis indicated that patients with CALR type-2 mutations or no detectable mutations had inferior survival compared to those with JAK2, MPL or CALR type- 1 or other less common CALR mutations (the median survival was 74vs 168 months, respectively [HR 2.990 (95% CI 1.935-4.619),P<0.001]. Therefore, patients were categorized into the high-risk with CALR type- 2 mutations or no detectable driver mutations and the low- risk without aforementioned mutations status. The DIPSS-Chinese molecular prognostic model was proposed by adopting mutation categories and DIPSS-Chinese risk group. The median survival of patients classified in low risk (132 subjects, 32.8% ), intermediate- 1 risk (143 subjects, 35.6%), intermediate- 2 risk (106 subjects, 26.4%) and high risk (21 subjects, 5.2%) were not reached, 156 (95% CI 117- 194), 60 (95% CI 28- 91) and 22 (95% CI 10- 33) months, respectively, and there was a statistically significant difference in overall survival among the four risk groups (P<0.001). There was significantly higher predictive power for survival according to the DIPSS-Chinese molecular prognostic model compared with the DIPSS-Chinese model (P=0.005, -2 log-likelihood ratios of 855.6 and 869
MPLW515L mutation in acute megakaryoblastic leukaemia.
Hussein, K; Bock, O; Theophile, K; Schulz-Bischof, K; Porwit, A; Schlue, J; Jonigk, D; Kreipe, H
2009-05-01
The thrombopoietin receptor gene (MPL) is expressed in megakaryocytes and exhibits the gain of function point mutation W515K/L in approximately 5% of patients with primary myelofibrosis/idiopathic myelofibrosis (PMF) representing one subtype of the chronic myeloproliferative disorders (myeloproliferative neoplasm). A series of primary and secondary acute myeloid leukaemias (AML) with megakaryoblastic phenotype and myelofibrosis unrelated to PMF (n=12) was analysed for the MPL(W515K/L) mutation by pyrosequencing. In three cases (25%), MPL(W515L) was found and in two of these a combination with trisomy 21 or the Philadelphia chromosome occurred. None of the secondary AML cases evolving from pre-existing PMF showed MPL(W515K/L) (n=4). We conclude that MPL(W515L) occurs in a considerable proportion of acute megakaryoblastic leukaemias with myelofibrosis unrelated to PMF.
ON012380: A Non-ATP Competitive Inhibitor of BCR-ABL for the Therapy of Imatinib-Resistant CMLs
2007-05-01
polycythemia vera (PV) as well as in some cases of essential thrombocythemia (ET) and chronic idiopathic myelofibrosis (CIMF), all of which are...in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell. 7(4):387-97. 20 Meydan N, Grunberger T
2018-02-15
Acute Biphenotypic Leukemia; Acute Lymphoblastic Leukemia; Acute Myeloid Leukemia; B-Cell Non-Hodgkin Lymphoma; Chronic Lymphocytic Leukemia; Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Hematologic and Lymphocytic Disorder; Hematopoietic Cell Transplantation Recipient; Myelodysplastic Syndrome; Primary Myelofibrosis; Secondary Myelofibrosis; T-Cell Non-Hodgkin Lymphoma; Thrombocytopenia; Venous Thromboembolism
A MODEL FOR POSTRADIATION STEM CELL KINETICS,
In polycythemic rats observed for 17 days postradiation (300 R, 250 KVP X-rays) it was noted that stem cell release diminished to 8 percent of the...correlate these findings with a kinetic model of erythropoiesis. It was suggested that the initial depression in stem cell release might be due to cellular
Lucewicz, A; Fisher, K; Henry, A; Welsh, A W
2016-02-01
Twin anemia-polycythemia sequence (TAPS) is recognized increasingly antenatally by the demonstration of an anemic twin and a polycythemic cotwin using the middle cerebral artery peak systolic velocity (MCA-PSV). While the MCA-PSV has been shown to correlate well with anemia in singleton fetuses, the evidence to support its use to diagnose fetal polycythemia appears to be less clear-cut. We aimed to evaluate fetal, neonatal and adult literature used to support the use of MCA-PSV for the diagnosis of polycythemia. Comprehensive literature searches were performed for ultrasound evidence of polycythemia in the human fetus, neonate and adult using key search terms. Only manuscripts in the English language with an abstract were considered for the review, performed in June 2014. Fifteen manuscripts were found for the human fetus, including 38 cases of TAPS. Nine of these defined fetal polycythemia as MCA-PSV < 0.8 multiples of the median (MoM), five used < 1.0 MoM and one used 0.8-1.0 MoM. Only two studies, involving a total of 15 cases, proposed a diagnostic level, acknowledging false-positive and -negative cases, though neither reported sensitivities or specificities. Six neonatal studies (96 neonates) demonstrated evidence of decreased cerebral velocities in polycythemia and a consequent increase with hemodilution. In the adult, five studies (57 polycythemic adults) demonstrated increased flow or velocity with hemodilution. Neither neonatal nor adult studies conclusively defined levels for screening for polycythemia. Despite widespread adoption of a cut-off of < 0.8 MoM in the published literature for the polycythemic fetus in TAPS, this is based upon minimal evidence, with unknown sensitivity and specificity. We recommend caution in excluding TAPS based purely upon the absence of a reduced MCA-PSV. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.
Tumor-associated erythrocytosis in a dog with nasal fibrosarcoma.
Couto, C G; Boudrieau, R J; Zanjani, E D
1989-01-01
Erythrocytosis (hematocrit, 79%) was diagnosed in an 8-year-old, neutered female, mixed-breed dog with an intranasal fibrosarcoma. Both serum and tumor erythropoietin (Ep) activities were elevated, as determined by the polycythemic exhypoxic mouse model, and the Ep activity was neutralized in that model by rabbit anti-Ep antibodies. Tumor resection normalized the hematocrit.
Dutta, Avik; Hutchison, Robert E; Mohi, Golam
2017-08-17
Myelofibrosis (MF) is a devastating blood disorder. The JAK2V617F mutation has been detected in ∼50% cases of MF. Elevated expression of high-mobility group AT hook 2 (HMGA2) has also been frequently observed in patients with MF. Interestingly, upregulation of HMGA2 expression has been found in association with the JAK2V617F mutation in significant cases of MF. However, the contribution of HMGA2 in the pathogenesis of MF remains elusive. To determine the effects of concurrent expression of HMGA2 and JAK2V617F mutation in hematopoiesis, we transduced bone marrow cells from Jak2 V617F knockin mice with lentivirus expressing Hmga2 and performed bone marrow transplantation. Expression of Hmga2 enhanced megakaryopoiesis, increased extramedullary hematopoiesis, and accelerated the development of MF in mice expressing Jak2 V617F Mechanistically, the data show that expression of Hmga2 enhances the activation of transforming growth factor-β1 (TGF-β1) and Cxcl12 pathways in mice expressing Jak2 V617F In addition, expression of Hmga2 causes upregulation of Fzd2, Ifi27l2a, and TGF-β receptor 2. Forced expression of Cxcl12, Fzd2, or Ifi27l2a increases megakaryocytic differentiation and proliferation in the bone marrow of Jak2 V617F mice, whereas TGF-β1 or Cxcl12 stimulation induces collagen deposition in the bone marrow mesenchymal stromal cells. Together, these findings demonstrate that expression of Hmga2 cooperates with Jak2 V617F in the pathogenesis of MF. © 2017 by The American Society of Hematology.
Goldin, Lynn R.; Kristinsson, Sigurdur Y.; Helgadottir, Elin A.; Samuelsson, Jan; Björkholm, Magnus
2008-01-01
Previous small studies have reported familial clustering of myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF). We identified 6217 PV, 2838 ET, 1172 MF, and 812 MPN unclassifiable (NOS) patients diagnosed in Sweden, 43 550 controls, and first-degree relatives of cases (n = 24 577) and controls (n = 99 542). Using a marginal survival model, we calculated relative risks (RRs) and 95% confidence intervals as measures of familial aggregation. Relatives of MPN patients had significantly increased risks of PV (RR = 5.7; 3.5-9.1), ET (RR = 7.4; 3.7-14.8), and MPN NOS (RR = 7.5; 2.7-20.8). Analyses stratified by type of first-degree relative revealed consistently higher risks for siblings, compatible with a model of recessive genetic inheritance, which can be confirmed only by identifying the susceptibility gene(s). Mean age at MPN diagnosis was not different (P = .20) for affected relatives of cases (57.5 years) versus controls (60.6 years), and risk of MPN by age was not different for parents versus offspring of MPN cases (P = .10), providing no support for anticipation. Relatives of MPN patients had a borderline increased risk of chronic myeloid leukemia (CML; RR = 1.9; 0.9-3.8; P = .09). Our findings of 5- to 7-fold elevated risk of MPNs among first-degree relatives of MPN patients support the hypothesis that common, strong, shared susceptibility genes predispose to PV, ET, MF, and possibly CML. PMID:18451307
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
2015-09-01
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). Copyright© Ferrata Storti Foundation.
Chemical-Induced Erythrocytosis in Wistar Rats: Assessment as a Model for Human Polycythemia.
1985-05-01
polycythemic condition are unusual features that are more typically found in polycythemia vera, an autonomous myeloproliferative disorder in man that results...polycythemia vera, an autonomous myeloproliferative disorder in man that results from clonal neoplasia of bone marrow stem cells. However, the data described...5 and stroma cell lines [55]. These diseases are commonly termed ’ myeloproliferative disorders’, or better, ’myelodysplastic disease’ which emphasizes
Pavlistova, Lenka; Izakova, Silvia; Zemanova, Zuzana; Bartuskova, Lucie; Langova, Martina; Malikova, Pavlina; Michalova, Kyra
2016-01-01
Constitutional translocations between sex chromosomes are rather rare in humans with breakpoints at Xp11 and Yq11 as the most frequent. Breakpoints on the short arm of the Y chromosome form one subgroup of t(X;Y), giving rise to a derived chromosome with the centromeres of both the X and Y chromosomes, dic(X;Y). Here, we report a rare congenital chromosomal aberration, 46,X,dic(X;Y)(p22.33;p11.32)[20]/45,X[10], in an adult male. Primary myelofibrosis, a malignant haematological disease, was diagnosed in a 63-year-old man following liver transplantation after hepatocellular carcinoma. By the analysis of the bone marrow sample, the karyotype 46,X,dic(X;Y)(p22.33;p11.32) was detected in all the mitoses analysed and verified with multicolour fluorescence in situ hybridization (mFISH). A cytogenetic examination of stimulated peripheral blood cells revealed the constitutional karyotype 46,X,dic(X;Y)(p22.33;p11.32)[20]/45,X[10]. The cell line 45,X was confirmed with FISH in 35 % of interphase nuclei. The SRY locus was present on the dicentric chromosome. A CGH/SNP array (Illumina) revealed a gain of 153,7 Mbp of the X chromosome and a 803-kbp microdeletion (including the SHOX gene), which were also confirmed with FISH. SHOX encodes a transcriptional factor that regulates the growth of the long bones. The deletion of the SHOX gene together with the Madelung deformity of the forearm and the short stature of the proband led to a diagnosis of Léri-Weill dyschondrosteosis (LWD). The gain of almost the whole X chromosome (153,7 Mbp) was considered a variant of Klinefelter syndrome (KS). The levels of gonadotropins and testosterone were consistent with gonadal dysfunction. A malformation of the right external ear was detected. We have reported a structural aberration of the sex chromosomes, dic(X;Y)(p22.33;p11.32). The related genomic imbalance is associated with two known hereditary syndromes, LWD and a KS variant, identified in our proband at an advanced age. Because the
Post retention and post/core shear bond strength of four post systems.
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).
Takahashi, Shuichiro; Tsumanuma, Riko; Aizawa, Keiko; Osakabe, Mitsumasa; Maeda, Kunihiko; Omoto, Ejiro
2016-01-01
The prognosis for myelodysplastic syndrome with bone marrow fibrosis (MDS-F) is worse than the prognosis of MDS without fibrosis. Hematopoietic stem cell transplantation (HSCT) is the only curative therapy; however, the indications and the procedures involved in HSCT remain unclear. We herein describe a 69-year-old Japanese man with MDS-F who received haploidentical HSCT and post-transplantation cyclophosphamide. Although the first HSCT resulted in secondary graft failure, the second HSCT using PTCy led to successful engraftment after early improvement in fibrosis. Since the incidence of graft failure is high in myelofibrosis patients, a secondary HSCT using PTCy may be successful if employed. PMID:27853082
Wang, Xiaoli; Zhang, Wei; Tripodi, Joseph; Lu, Min; Xu, Mingjiang; Najfeld, Vesna; Li, Yan
2010-01-01
Because primary myelofibrosis (PMF) originates at the level of the pluripotent hematopoietic stem cell (HSC), we examined the effects of various therapeutic agents on the in vitro and in vivo behavior of PMF CD34+ cells. Treatment of PMF CD34+ cells with chromatin-modifying agents (CMAs) but not hydroxyurea, Janus kinase 2 (JAK2) inhibitors, or low doses of interferon-α led to the generation of greater numbers of CD34+ chemokine (C-X-C motif) receptor (CXCR)4+ cells, which were capable of migrating in response to chemokine (C-X-C motif) ligand (CXCL)12 and resulted in a reduction in the proportion of hematopoietic progenitor cells (HPCs) that were JAK2V617F+. Furthermore, sequential treatment of PMF CD34+ cells but not normal CD34+ cells with decitabine (5-aza-2′-deoxycytidine [5azaD]), followed by suberoylanilide hydroxamic acid (SAHA; 5azaD/SAHA), or trichostatin A (5azaD/TSA) resulted in a higher degree of apoptosis. Two to 6 months after the transplantation of CMAs treated JAK2V617F+ PMF CD34+ cells into nonobese diabetic/severe combined immunodeficient (SCID)/IL-2Rγnull mice, the percentage of JAK2V617F/JAK2total in human CD45+ marrow cells was dramatically reduced. These findings suggest that both PMF HPCs, short-term and long-term SCID repopulating cells (SRCs), are JAK2V617F+ and that JAK2V617F+ HPCs and SRCs can be eliminated by sequential treatment with CMAs. Sequential treatment with CMAs, therefore, represents a possible effective means of treating PMF at the level of the malignant SRC. PMID:20858855
Ghosh, Manik C.; Zhang, De-Liang; Jeong, Suh Young; Kovtunovych, Gennadiy; Ollivierre-Wilson, Hayden; Noguchi, Audrey; Tu, Tiffany; Senecal, Thomas; Robinson, Gabrielle; Crooks, Daniel R.; Tong, Wing-Hang; Ramaswamy, Kavitha; Singh, Anamika; Graham, Brian B.; Tuder, Rubin M.; Yu, Zu-Xi; Eckhaus, Michael; Lee, Jaekwon; Springer, Danielle A.; Rouault, Tracey A.
2013-01-01
SUMMARY Iron regulatory proteins 1 and 2 (Irps) post-transcriptionally control the expression of transcripts that contain iron responsive element (IRE) sequences, including ferritin, ferroportin, transferrin receptor and hypoxia inducible factor 2α (HIF2α). We report here that mice with targeted deletion of Irp1 developed pulmonary hypertension and polycythemia that was exacerbated by a low iron diet. Hematocrits increased to 65% in iron-starved mice, and many polycythemic mice died of abdominal hemorrhages. Irp1 deletion enhanced HIF2α protein expression in kidneys of Irp1−/− mice, which led to increased erythropoietin (EPO) expression, polycythemia and concomitant tissue iron deficiency. Increased HIF2α expression in pulmonary endothelial cells induced high expression of endothelin-1, likely contributing to the pulmonary hypertension of Irp1−/− mice. Our results reveal why anemia is an early physiological consequence of iron deficiency, highlight the physiological significance of Irp1 in regulating erythropoiesis and iron distribution, and provide important insights into the molecular pathogenesis of pulmonary hypertension. PMID:23395173
Use of isovolemic hemodilution in the management of arterial ischemia in patients with polycythemia.
Shah, D M; Buchbinder, D; Balko, A; Karmody, A M; Leather, R P
1981-08-01
The management of patients with both polycythemia and limb-threatening ischemia presents many difficulties because in this population, vascular surgical procedures carry a particularly high incidence of hemorrhagic and thromboembolic complications. We evaluated the use of acute isovolemic hemodilution in 12 polycythemic patients who required urgent surgery due to severe ischemia and threatened limb loss. Within 48 hours, blood was withdrawn in units of 500 ml and simultaneously replaced with 1,500 ml of lactated Ringer's solution until a hematocrit of 35 to 40 percent was achieved. After hemodilution, two patients had such a marked improvement that no further therapeutic measures were required immediately. Four patients showed definite improvement in pulmonary vascular resistance tracings and segmental Doppler pressures, but ischemia was not fully ameliorated. These patients together with the remaining six patients underwent vascular surgery within 1 to 14 days after hemodilution. A hematocrit of 32 to 40 percent was maintained during the perioperative period. All arterial reconstructions were successfully completed and there were no perioperative failures. No pulmonary emboli, myocardial infarctions, or deaths occurred in this period. These results indicate that in polycythemic patients, urgent vascular surgery can be performed more safely with the concomitant use of acute isovolemic hemodilution.
The "Post-Post Period" and Environmental Education Research
ERIC Educational Resources Information Center
McKenzie, Marcia
2005-01-01
Described as "post-experimental" and of the "post-post period," the current moment in social science research is typified by multi-voiced texts, researcher reflexivity, cultural criticism, and experimental works; characteristics in keeping with post-structurally informed understandings of social science research as contingent, evolving and messy.…
Stegelmann, Frank; Bullinger, Lars; Griesshammer, Martin; Holzmann, Karlheinz; Habdank, Marianne; Kuhn, Susanne; Maile, Carmen; Schauer, Stefanie; Döhner, Hartmut; Döhner, Konstanze
2010-01-01
Single-nucleotide polymorphism arrays allow for genome-wide profiling of copy-number alterations and copy-neutral runs of homozygosity at high resolution. To identify novel genetic lesions in myeloproliferative neoplasms, a large series of 151 clinically well characterized patients was analyzed in our study. Copy-number alterations were rare in essential thrombocythemia and polycythemia vera. In contrast, approximately one third of myelofibrosis patients exhibited small genomic losses (less than 5 Mb). In 2 secondary myelofibrosis cases the tumor suppressor gene NF1 in 17q11.2 was affected. Sequencing analyses revealed a mutation in the remaining NF1 allele of one patient. In terms of copy-neutral aberrations, no chromosomes other than 9p were recurrently affected. In conclusion, novel genomic aberrations were identified in our study, in particular in patients with myelofibrosis. Further analyses on single-gene level are necessary to uncover the mechanisms that are involved in the pathogenesis of myeloproliferative neoplasms. PMID:20015882
Activity of Pure Streptovaricins and Fractionated Streptovaricin Complex Against Friend Virus
Horoszewicz, Julius S.; Rinehart, Kenneth L.; Leong, Susan S.; Carter, William A.
1975-01-01
Chromatographic fractionation of streptovaricin complex yields two stable components enriched (4- to 16-fold) in activity directed against the polycythemic strain of Friend virus; both components apparently contain no streptovaricins. When compared with their unfractionated parent streptovaricin complex, eight individual intact streptovaricins (A through G and J) show at least a 30-fold reduction in antiviral activity. These results further support the conclusion that the diversified biological properties of streptovaricin complex probably reside in different molecular structures. PMID:237470
2018-04-04
Adult Hodgkin Lymphoma; Adult Myelodysplastic Syndrome; Blast Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Childhood Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Childhood Hodgkin Lymphoma; Childhood Myelodysplastic Syndrome; Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Myelofibrosis; Primary Myelofibrosis; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Non-Hodgkin Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Non-Hodgkin Lymphoma; Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Refractory Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Refractory Non-Hodgkin Lymphoma
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.
Correspondence between fiber post and drill dimensions for post canal preparation.
Portigliatti, Ricardo Pablo; Tumini, José Luis; Bertoldi Hepburn, Alejandro Daniel; Aromando, Romina Flavia; Olmos, Jorge Lorenzo
2017-12-01
To compare fiber posts of several calibers and trademarks to their corresponding root canal preparation drills. Three widely used endodontic post brands and their drills were evaluated: Exacto, ParaPost Taper Lux, and Macro-Lock Illusion X-RO. Fiber posts and drills were microphotographed with a scanning electron microscope and images were analyzed using ImageJ image processing software. Fiber post diameter on apical extreme (Pd0), fiber post diameter at 5 mm from the apical extreme (Pd5), drill diameter on apical extreme (Dd0) and drill diameter at 5 mm from the apical extreme (Dd5) were analyzed. The data were statistically analyzed using student t-test. Exacto posts 0.5 showed larger dimensions than their corresponding drills (P< 0.05) at Pd0. Macro-Lock posts showed no significant differences vs. their drills at Pd0 in any of the studied groups. ParaPost drills 4.5, 5 and 5.5 were statistically significantly larger than their posts at Dd0 (P< 0.05). Exacto posts 0.5 and 1 showed larger dimensions than their drills measured at Pd5 (P< 0.05). Exacto posts number 2 showed smaller calibers than their corresponding drills at Pd5 (P< 0.05). Macro-Lock drills number 4 and ParaPost drills number 5 were larger than their posts at Dd5 (P< 0.05). Poor spatial correspondence between post and drill dimensions can adversely affect the film thickness of the resin cement, diminishing bond strength due to polymerization shrinkage. The lack of correspondence in size between posts and drills may lead to the formation of empty chambers between the post and endodontic obturation with excessive luting cement thickness, thus inducing critical C-Factor stresses.
Post-traumatic Stress Disorder Post Partum
Schwab, W.; Marth, C.; Bergant, A. M.
2012-01-01
Traumatic birth experiences may lead to serious psychological impairment. Recent studies show that a considerable number of women can develop post-traumatic stress disorder (PTSD), in some cases in a subsyndromal form. Until now, the possibility that postpartum psychological symptoms might be a continuum of a pre-existing disorder in pregnancy has rarely been considered. This study therefore aimed to evaluate the proportion of women who develop post-traumatic stress disorder as a result of childbirth. Materials and Methods: 56 multiparous women were recruited for the study. The diagnosis of PTSD was made according to the criteria for psychological disorders in the DSM-IV (Diagnostics and Statistical Manual of Mental Disorders). The data were collected in structured interviews in the 30th to 38th week of gestation and in the 6th week post partum. Results: Of the 56 women participating, 52 (93 %) completed the survey. Uncontrolled results showed that 21.15 % of the multiparous women met the full diagnostic PTSD criteria in the 6th week post partum. After the exclusion of all cases already characterised by all criteria or a subsyndromal form of PTSD caused by previous traumatisation, the PTSD rate was below 8 % at 6 weeks postpartum (= incidence rate of PTSD post partum). Conclusions: The present study is the first prospective longitudinal study to demonstrate the occurrence of full criteria PTSD in multiparous women as a result of childbirth after having excluded pre-existing PTSD. The results of our study show a high prevalence rate of PTSD during pregnancy. A number of women report all aspects of post-traumatic stress disorder as a result of childbirth. PMID:25253905
Badelita, S; Dobrea, C; Colita, A; Dogaru, M; Dragomir, M; Jardan, C; Coriu, D
2015-01-01
Multiple myeloma and JAK2 positive chronic myeloproliferative neoplasms are hematologic malignancies with a completely different cellular origin. Two cases of simultaneous occurrence of multiple myeloma, one with primary myelofibrosis and another one with essential thrombocythemia are reported in this article. In such cases, an accurate diagnosis requires a molecular testing, including gene sequencing and differential diagnosis of pancytosis associated with splenic amyloidosis. In general, in such cases, of two coexisting malignant hematologic diseases, the treatment of the most aggressive one is recommended. For our two cases, it was decided to start a Velcade based therapy. The main concern was the medullar toxicity, especially when a multiple myeloma was associated with a primary myelofibrosis. Abbreviations:JAK2 = Janus kinase 2 gene, PMF = primary myelofibrosis, MPNs = myeloproliferative neoplasms, ET = essential thrombocythemia, PV = polycythemia vera, MM = multiple myeloma, WBC = white blood cells, Hb = haemoglobin, Ht = haematocrit, Plt = platelets, BMB = bone marrow biopsy, CBC = blood cell count, CT = computerized tomography, LAP = leukocyte alkaline phosphatase, MGUS = monoclonal gammopathy of undetermined significance. PMID:25914740
Glembotsky, Ana C; Korin, Laura; Lev, Paola R; Chazarreta, Carlos D; Marta, Rosana F; Molinas, Felisa C; Heller, Paula G
2010-05-01
To evaluate the frequency of MPL W515L, W515K and S505N mutations in essential thrombocythemia (ET) and primary myelofibrosis (PMF) and to determine whether MPLW515L leads to impaired Mpl expression, constitutive STAT3 and STAT5 activation and enhanced response to thrombopoietin (TPO). Mutation detection was performed by allele-specific PCR and sequencing. Platelet Mpl expression was evaluated by flow cytometry, immunoblotting and real-time RT-PCR. Activation of STAT3 and STAT5 before and after stimulation with increasing concentrations of TPO was studied by immunoblotting. Plasma TPO was measured by ELISA. MPLW515L was detected in 1 of 100 patients with ET and 1 of 11 with PMF. Platelets from the PMF patient showed 100% mutant allele, which was <50% in platelets from the ET patient, who also showed the mutation in granulocytes, monocytes and B cells. Mpl surface and total protein expression were normal, and TPO levels were mildly increased in the MPLW515L-positive ET patient, while MPL transcripts did not differ from controls in both MPLW515L-positive patients. Constitutive STAT3 and STAT5 phosphorylation was absent and dose response to TPO-induced phosphorylation was not enhanced. The low frequency of MPL mutations in this cohort is in agreement with previous studies. The finding of normal Mpl levels in MPLW515L-positive platelets indicates this mutation does not lead to dysregulated Mpl expression, as frequently shown for myeloproliferative neoplasms. The lack of spontaneous STAT3 and STAT5 activation and the normal response to TPO is unexpected as MPLW515L leads to constitutive receptor activation and hypersensitivity to TPO in experimental models.
2017-07-24
Primary Myelofibrosis; Thrombocythemia, Essential; Thrombocytosis; Myeloproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Blood Coagulation Disorders; Blood Platelet Disorders; Hemorrhagic Disorders
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…
Vadachkoriia, N R; Mandzhavidze, N A; Gumberidze, N Sh
2009-02-01
The article discusses the current state of restoration techniques of root canal treatment. Nowadays, technical progress allows manufacturers to develop flexible fiberglass posts, aspiring not only to an excellent aesthetics and mechanical properties (first of all, in comparison with metal and cast posts), but also to maintenance of their radio density and a wide range of forms. Growth of fiberglass posts popularity testifies to their clinical efficiency that also is confirmed by results of long-term researches. Introduction of fiberglass posts in a dental practice has rendered huge influence on restoration techniques of root canal treatment. Convincing factors of fiberglass posts superiority provide restoration the appearance similar with the natural dentition; possess close to dentine elasticity; creation of monolithic structure with hard tooth tissues and composite cement, posts, in case of need, can be easily adjusted on length, adhesive linkage of posts gives them additional stability. Modern researches have confirmed that only elastic, namely carbon fiber and the fiberglass posts made of modern technologies possess similar physical properties, as tooth structure. They can create reliable biomimetic design; solve a complex of aesthetic and functional restoration problems.
Polycythemia and Thrombocytosis.
Parnes, Aric; Ravi, Arvind
2016-12-01
Myeloproliferative neoplasms (MPNs) are diseases of excess cell proliferation from bone marrow precursors. Two classic MPNs, polycythemia vera (PV) and essential thrombocytosis (ET), are conditions of excess proliferation of red blood cells and platelets, respectively. Although PV and ET involve different cells in the myeloid lineage, their clinical presentations have shared features, consistent with overlapping mutations in growth factor signaling. The management of both diseases involves minimizing the risk of thrombotic and hemorrhagic complications. Both PV and ET can progress to myelofibrosis or acute myeloid leukemia, portending a poor prognosis. MPNs can also present as primary myelofibrosis. Copyright © 2016 Elsevier Inc. All rights reserved.
Post driver for steel guardrail posts : final report.
DOT National Transportation Integrated Search
2003-01-01
The objective of this research project was to locate an existing product, or if necessary, design and develop a product for use as a driver for steel guardrail posts. The post driver would also be able to minimize the bending and twisting of the stee...
Fludarabine Based Conditioning for Allogeneic Transplantation for Advanced Hematologic Malignancies
2017-10-25
Acute Myeloid Leukemia; Acute Leukemia; Chronic Myelogenous Leukemia; Malignant Lymphoma; Hodgkin's Disease; Multiple Myeloma; Lymphocytic Leukemia; Myeloproliferative Disorder; Polycythemia Vera; Myelofibrosis; Aplastic Anemia
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.
A laboratory comparison of individual Targis/Vectris posts with standard fiberglass posts.
Corsalini, Massimo; Genovese, Katia; Lamberti, Luciano; Pappalettere, Carmine; Carella, Mauro; Carossa, Stefano
2007-01-01
This article presents an in vitro analysis of a specific occlusal loading test on endodontically treated teeth restored with 2 different composite post materials. Individual, customized posts (IFPs) were compared to standard fiberglass posts (SFPs). The selected IFPs (standard cylindric Targis/Vectris posts) were compared to SFPs (Conic 6% Post, Ghimas). The posts were first subjected to a 3-point bending test to compare their flexural elastic properties. They were then used to restore 22 endodontically treated artificial maxillary central incisors and subjected to a specific occlusal loading simulation test. The loading test showed that IFP restorations performed better than SFP restorations. A clinical evaluation of this laboratory observation is suggested.
2016-01-28
Acute Myelogenous Leukemia; Acute Lymphocytic Leukemia; Chronic Myelogenous Leukemia; Chronic Lymphocytic Leukemia; Myelodysplasia; Non-Hodgkin's Lymphoma; Hodgkin's Disease; Multiple Myeloma; Myelofibrosis; Anemia, Aplastic; Hemoglobinuria, Paroxysmal
2018-02-13
Myelodysplastic Syndrome; Acute Myeloid Leukemia; Myeloproliferative Disorders; Acute Lymphocytic Leukemia; Acute Promyelocytic Leukemia; Acute Leukemia; Chronic Myelogenous Leukemia; Myelofibrosis; Chronic Myelomonocytic Leukemia; Juvenile Myelomonocytic Leukemia
Iliac crest tap; Sternal tap; Leukemia - bone marrow aspiration; Aplastic anemia - bone marrow aspiration; Myelodysplastic syndrome - bone marrow aspiration; Thrombocytopenia - bone marrow aspiration; Myelofibrosis - bone marrow aspiration
Schnittger, Susanne; Bacher, Ulrike; Eder, Christiane; Dicker, Frank; Alpermann, Tamara; Grossmann, Vera; Kohlmann, Alexander; Kern, Wolfgang; Haferlach, Claudia; Haferlach, Torsten
2012-01-01
We investigated 15,542 patients with suspected BCR-ABL1- negative myeloproliferative or myelodysplastic/myeloproliferative neoplasm (including 359 chronic myelomonocytic leukemia) by a molecular marker set. JAK2V617F was detected in the suspected categories as follows: polycythemia vera 88.3%, primary myelofibrosis 53.8%, essential thrombocythemia 50.2%, and not further classifiable myeloproliferative neoplasms 38.0%. JAK2 exon 12 mutations were detected in 40.0% JAK2V617F-negative suspected polycythemia vera, MPLW515 mutations in 13.2%JAK2V617F-negative primary myelofibrosis and 7.1% JAK2V617F-negative essential thrombocythemia. TET2 mutations were distributed across all entities but were most frequent in suspected chronic myelomonocytic leukemia (77.8%). CBL mutations were identified in suspected chronic myelomonocytic leukemia (13.9%), primary myelofibrosis (8.0%), and not further classifiable myeloproliferative neoplasm (7.0%). This leads to a stepwise workflow for suspected myeloproliferative neoplasms starting with JAK2V617F and investigating JAK2V617F-negative patients for JAK2 exon 12 or MPL mutations, respectively. In cases in which a myeloproliferative neoplasm cannot be established, analysis for TET2, CBL and EZH2 mutations may be indicated. PMID:22511494
Context Specificity of Post-Error and Post-Conflict Cognitive Control Adjustments
Forster, Sarah E.; Cho, Raymond Y.
2014-01-01
There has been accumulating evidence that cognitive control can be adaptively regulated by monitoring for processing conflict as an index of online control demands. However, it is not yet known whether top-down control mechanisms respond to processing conflict in a manner specific to the operative task context or confer a more generalized benefit. While previous studies have examined the taskset-specificity of conflict adaptation effects, yielding inconsistent results, control-related performance adjustments following errors have been largely overlooked. This gap in the literature underscores recent debate as to whether post-error performance represents a strategic, control-mediated mechanism or a nonstrategic consequence of attentional orienting. In the present study, evidence of generalized control following both high conflict correct trials and errors was explored in a task-switching paradigm. Conflict adaptation effects were not found to generalize across tasksets, despite a shared response set. In contrast, post-error slowing effects were found to extend to the inactive taskset and were predictive of enhanced post-error accuracy. In addition, post-error performance adjustments were found to persist for several trials and across multiple task switches, a finding inconsistent with attentional orienting accounts of post-error slowing. These findings indicate that error-related control adjustments confer a generalized performance benefit and suggest dissociable mechanisms of post-conflict and post-error control. PMID:24603900
Post-traumatic stress disorder in U.S. soldiers with post-traumatic headache.
Rosenthal, Jacqueline F; Erickson, Jay C
2013-01-01
To determine the impact of post-traumatic stress disorder (PTSD) on headache characteristics and headache prognosis in U.S. soldiers with post-traumatic headache. PTSD and post-concussive headache are common conditions among U.S. Army personnel returning from deployment. The impact of comorbid PTSD on the characteristics and outcomes of post-traumatic headache has not been determined in U.S. Army soldiers. A retrospective cohort study was conducted among 270 consecutive U.S. Army soldiers diagnosed with post-traumatic headache at a single Army neurology clinic. All subjects were screened for PTSD at baseline using the PTSD symptom checklist. Headache frequency and characteristics were determined for post-traumatic headache subjects with and without PTSD at baseline. Headache measures were reassessed 3 months after the baseline visit, and were compared between groups with and without PTSD. Of 270 soldiers with post-traumatic headache, 105 (39%) met screening criteria for PTSD. There was no significant difference between subjects with PTSD and those without PTSD with regard to headache frequency (17.2 vs 15.7 headache days per month; P = .15) or chronic daily headache (58.1% vs 52.1%; P = .34). Comorbid PTSD was associated with higher headache-related disability as measured by the Migraine Disability Assessment Score. Three months after the baseline neurology clinic visit, the number of subjects with at least 50% reduction in headache frequency was similar among post-traumatic headache cases with and without PTSD (25.9% vs 26.8%). PTSD is prevalent among U.S. Army soldiers with post-traumatic headache. Comorbid PTSD is not associated with more frequent headaches or chronic daily headache in soldiers evaluated at a military neurology clinic for chronic post-traumatic headache. Comorbid PTSD does not adversely affect short-term headache outcomes, although prospective controlled trials are needed to better assess this relationship. © 2013 American Headache
Zoppoli, Gabriele; Bianchi, Federico; Bruzzone, Andrea; Calvia, Alessandro; Oneto, Caterina; Passalia, Caterina; Balleari, Enrico; Bedognetti, Davide; Ponomareva, Elena; Nazzari, Elena; Castelletti, Lara; Castellan, Lucio; Minuto, Francesco; Ghio, Riccardo; Ferone, Diego
2012-06-01
Polycythemia associated with acromegaly is usually caused by the systemic manifestations of the disease, such as sleep-apnea or concomitant erythropoietin-secreting kidney tumors. The recognition of underlying pathologies requires a thorough diagnostic process. We report a unique case of acromegaly with polycythemia, not caused by commonly described manifestations of the disease, and receding with octreotide therapy. The medical history of 141 acromegalic patients followed by the Endocrinology Unit of the San Martino University Hospital in Genoa has been also reviewed, together with the literature evidence for similar cases. The diagnostic workflow and 2-years follow-up of a 43-years old acromegalic, polycythemic man with a history of past smoking, moderate hypertension, and mental retardation are described. The hematological parameters of our cohort was retrospectively compared with those of a healthy, age/gender-related control group as well. Therapy with octreotide LAR, 20 mg i.m. q28d was begun soon after diagnosis of acromegaly in the polycythemic patient. Haematocrit level, hormonal setting, as well as pituitary tumor size and visual perimetry during treatment were recorded. Octreotide LAR treatment normalized hormonal alterations, as well as hematological parameters. Polycythemia has not recurred after 2 years of therapy. The median hemoglobin and hematocrit levels of the retrospectively analyzed cohort of acromegalic were significantly lower than normal ranges of a healthy, age/sex- related control population. In conclusions, polycythemia can be a direct, albeit rare, secondary manifestation of acromegaly, that must be considered during the diagnostic work-up of acromegalic patients presenting with such disorder.
Braga, Neilor Mateus Antunes; Souza-Gabriel, Aline Evangelista; Messias, Danielle Cristine Furtado; Rached-Junior, Fuad Jacob Abi; Oliveira, Camila Fávero; Silva, Ricardo Gariba; Silva-Sousa, Yara T Corrêa
2012-01-01
The aim of this study was to assess the influence of surface pretreatments of fiber-reinforced posts on flexural strength (FS), modulus of elasticity (ME) and morphology of these posts, as well as the bond strength (BS) between posts and core material. Fifty-two fiber posts (smooth and serrated) were assigned to 4 groups (n=13): no treatment (control), 10% hydrogen peroxide (HP) for 10 min (HP-10), 24% HP for 1 min (HP-24) and airborne-particle abrasion (Al(2)O(3)). To evaluate FS and ME, a 3-point bending test was performed. Three posts of each group were examined by scanning electron microscopy. Composite resin was used as the core build-up and samples were sectioned to obtain microtensile sticks. Data were analyzed by ANOVA and Tukey's test (α=0.05). For FS, significant differences were observed between posts type and surface pretreatment (p<0.05), with the highest means for the smooth posts. Al2O3 provided higher FS than HP-24. Al(2)O(3) promoted higher ME than HP-24 and control. SEM images revealed partial dissolution of the resin matrix in all treated groups. The smooth posts had higher BS and FS than serrated posts (p<0.05). Mechanical properties of the glass fiber posts and the bond strength between posts and composite material were not altered by the surface treatments, except for airborne-particle abrasion that increased the post elastic modulus.
2014-09-03
Chronic Myeloproliferative Disorders; Graft Versus Host Disease; Infection; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Neoplasms; Precancerous Condition; Secondary Myelofibrosis; Small Intestine Cancer
10. FLOOR 1; CENTER POST AND POSTS UNDER STONE BEAMS ...
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
1. Post card view of the bridge, c. 1910. Post ...
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
The Relative Importance of Post-Acute Care and Readmissions for Post-Discharge Spending.
Huckfeldt, Peter J; Mehrotra, Ateev; Hussey, Peter S
2016-10-01
To understand what patterns of health care use are associated with higher post-hospitalization spending. Medicare hospital, skilled nursing, inpatient rehabilitation, and home health agency claims, and Medicare enrollment data from 2007 and 2008. For 10 common inpatient conditions, we calculated variation across hospitals in price-standardized and case mix-adjusted Medicare spending in the 30 days following hospital discharge. We estimated the fraction of spending differences between low- and high-spending hospitals attributable to readmissions versus post-acute care, and within post-acute care between inpatient rehabilitation facility (IRF) versus skilled nursing facility (SNF) use. For each service, we distinguished between differences in probability of use and spending conditional on use. We identified index hospital claims and examined hospital and post-acute care occurring within a 30-day period following hospital discharge. For each Medicare Severity Diagnosis-Related Group (MS-DRG) at each hospital, we calculated average price-standardized Medicare payments for readmissions, SNFs, IRFs, and post-acute care overall (also including home health agencies and long-term care hospitals). There was extensive variation across hospitals in Medicare spending in the 30 days following hospital discharge. For example, the interquartile range across hospitals ranged from $1,245 for chronic obstructive pulmonary disease to over $4,000 for myocardial infarction MS-DRGs. The proportion of differences attributable to readmissions versus post-acute care differed across conditions. For myocardial infarction, 74 to 93 percent of the variation was due to readmissions. For hip and femur procedures and joint replacement, 72 to 92 percent of the variation was due to differences in post-acute care spending. There was also variation in the relative importance of the type of post-acute spending. For hip and femur procedures, joint replacement, and stroke, whether patients received IRF
Post-Traumatic Stress Disorder
... U V W X Y Z Post-Traumatic Stress Disorder Share: © Matthew Lester Post-traumatic stress disorder (PTSD) is an anxiety disorder that can ... military combat. For Consumers General Information Post-Traumatic Stress Disorder ( NIMH ) Anxiety Information Stress Information Depression Information ...
Myeloproliferative Neoplasms (MPNs) Patient Registry
2017-10-27
Primary Myelofibrosis; Polycythemia Vera; Essential Thrombocythemia; Mastocytosis; Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative; Leukemia, Myelomonocytic, Juvenile; Chronic Eosinophilic Leukemia-not Otherwise Specified; Myelodysplastic-Myeloproliferative Diseases; Neoplasms; Leukemia, Myelomonocytic, Chronic
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…
Genetics Home Reference: primary myelofibrosis
... 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, ...
ERIC Educational Resources Information Center
Span, Christopher M.
2015-01-01
This chapter details how slavery, segregation, and racism impacted the educational experiences of African Americans from the colonial era to the present. It argues that America has yet to be a truly post-slavery and post-segregation society, let alone a post-racial society.
Neves, Celestino; Alves, Marta; Delgado, Luís; Medina, J Luís
2009-01-01
In the post-partum period the immune alterations are associated with the multiple autoimmune diseases relapse. After birth, immune-tolerance variation slowly disappear, and is observed a return to a normal state - after an exacerbation period - of autoimmune reactivity, during which a great increase in T cells and autoantibodies is observed. In this period - 3 to 9 months after birth - the thyroid autoimmune disease relapses or reappears. The reactivation of the immune system in the post-partum period unchains an acute phase of celular destruction which characterizes the post-partum thyroiditis.
Fabricating fiber-reinforced composite posts.
Manhart, Jürgen
2011-03-01
Endodontic posts do not increase the strength of the remaining tooth structure in endodontically treated teeth. On the contrary, depending on the post design employed (tapered versus parallel-sided), the root can be weakened relative to the amount of tooth removed during preparation. In many cases, if there has been a high degree of damage to the clinical crown, conservative preparation for an anatomic tapered (biomimetic) post with the incorporation of a ferrule on solid tooth structure is necessary to protect the reaming root structure as well as for the long-term retention of the composite resin core and the definitive restoration. Adhesively luted endodontic posts reinforced with glass or quartz fiber lead to better homogeneous tension distribution when loaded than rigid metal or zirconium oxide ceramic posts. Fiber-reinforced posts also possess advantageous optical properties over metal or metal oxide post systems. The clinician should realize that there are admittedly substantial differences in the mechanical loading capacity of the different fiber-reinforced endodontic posts and should be aware of such differences in order to research and select a suitable post system for use.
Comprehensive review of JAK inhibitors in myeloproliferative neoplasms
Sonbol, Mohamad Bassam; Firwana, Belal; Zarzour, Ahmad; Morad, Mohammad; Rana, Vishal
2013-01-01
Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem-cell disorders, characterized phenotypically by the abnormal accumulation of mature-appearing myeloid cells. Polycythemia vera, essential thrombocythemia, primary myelofibrosis (also known as ‘BCR-ABL1-negative’ MPNs), and chronic myeloid leukemia (CML) are the primary types of MPNs. After the discovery of the BCR-ABL1 fusion protein in CML, several oncogenic tyrosine kinases have been identified in ‘BCR-ABL1-negative’ MPNs, most importantly, JAK2V617F mutation. The similarity in the clinical characteristics of the BCR-ABL1-negative MPN patients along with the prevalence of the Janus kinase mutation in this patient population provided a strong rationale for the development of a new class of pharmacologic inhibitors that target this pathway. The first of its class, ruxolitinib, has now been approved by the food and drug administration (FDA) for the management of patients with intermediate- to high-risk myelofibrosis. Ruxolitinib provides significant and sustained improvements in spleen related and constitutional symptoms secondary to the disease. Although noncurative, ruxolitinib represents a milestone in the treatment of myelofibrosis patients. Other types of JAK2 inhibitors are being tested in various clinical trials at this point and may provide better efficacy data and safety profile than its predecessor. In this article, we comprehensively reviewed and summarized the available preclinical and clinical trials pertaining to JAK inhibitors. PMID:23610611
Philadelphia chromosome-negative myeloproliferative disorders: biology and treatment.
Hoffman, Ronald; Prchal, Josef T; Samuelson, Scott; Ciurea, Stefan O; Rondelli, Damiano
2007-01-01
The Philadelphia chromosome (Ph)-negative myeloproliferative disorders (MPDs) include essential thrombocythemia (ET), idiopathic myelofibrosis (IMF), and polycythemia vera (PV). All of these disorders are clonal hematologic malignancies originating at the level of the pluripotent hematopoietic stem cell. Recently, activating mutations of the intracellular cytokine-signaling molecule JAK2 have been identified in > 90% of patients with PV and in 50% of those with IMF and ET. In addition, a mutation of the thrombopoietin receptor, MPLW515L, has been documented in some patients with IMF. Both mutations activate JAK-STAT signaling pathways and likely play a role in disease progression. Both ET and PV are associated with prolonged clinical courses associated with frequent thrombotic and hemorrhagic events, and progression to myelofibrosis and acute leukemia. IMF has a much poorer prognosis and is associated with cytopenias, splenomegaly, extramedullary hematopoiesis, and bone marrow fibrosis. Stratification of risk for the development of complications from Ph-negative MPDs has guided the identification of appropriate therapies for this population. Intermediate/high-risk IMF or myelofibrosis after ET or PV is associated with a sufficiently poor prognosis to justify the use of allogeneic stem cell transplantation, which is capable of curing such patients. Reduced-intensity conditioning in preparation for allogeneic stem cell transplantation has permitted older patients with IMF to undergo transplantation with increasing success.
Bernstein, Daniel J; Lange, Tanja
2017-09-13
Cryptography is essential for the security of online communication, cars and implanted medical devices. However, many commonly used cryptosystems will be completely broken once large quantum computers exist. Post-quantum cryptography is cryptography under the assumption that the attacker has a large quantum computer; post-quantum cryptosystems strive to remain secure even in this scenario. This relatively young research area has seen some successes in identifying mathematical operations for which quantum algorithms offer little advantage in speed, and then building cryptographic systems around those. The central challenge in post-quantum cryptography is to meet demands for cryptographic usability and flexibility without sacrificing confidence.
NASA Astrophysics Data System (ADS)
Bernstein, Daniel J.; Lange, Tanja
2017-09-01
Cryptography is essential for the security of online communication, cars and implanted medical devices. However, many commonly used cryptosystems will be completely broken once large quantum computers exist. Post-quantum cryptography is cryptography under the assumption that the attacker has a large quantum computer; post-quantum cryptosystems strive to remain secure even in this scenario. This relatively young research area has seen some successes in identifying mathematical operations for which quantum algorithms offer little advantage in speed, and then building cryptographic systems around those. The central challenge in post-quantum cryptography is to meet demands for cryptographic usability and flexibility without sacrificing confidence.
Boone, K J; Murchison, D F; Schindler, W G; Walker, W A
2001-12-01
Many endodontic sealers contain constituents that have been shown to inhibit the polymerization of resin cements. This may be important when prefabricated posts are cemented at the same appointment as root canal obturation. This study evaluated the effects of cementing posts with a resin cement immediately or at a delayed time period after obturation using Roth's 801 Elite Grade or AH26 sealer cements. The contribution of mechanical post-space preparation was also assessed as a critical variable. One hundred twenty extracted canines were randomly divided into eight experimental groups. The variables evaluated were the order of post preparation (either before or after obturation), the type of sealer used, and the time of post cementation. All teeth received a stainless steel #6 Parapost XP cemented with a resin cement, Panavia 21. Each experimental group underwent tensile testing for retention using an Instron universal testing machine. For both sealers posts cemented in teeth in which the canal was obturated before post-space preparation and thus had sealer-contaminated dentin removed by the space preparation procedure had significantly higher retentive values than those obturated after post-space preparation in which contaminated dentin might remain. Sealer used and time of cementation had no specific effect on retention. Achieving a clean, "freshened" dentinal surface during mechanical post-space preparation seems to be a critical variable for post retention when a resin cement is used.
Pemetrexed Disodium in the Cerebrospinal Fluid of Patients With Leptomeningeal Metastases
2017-03-15
Brain and Central Nervous System Tumors; Chronic Myeloproliferative Disorders; Leukemia; Lymphoma; Lymphoproliferative Disorder; Metastatic Cancer; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Precancerous Condition; Secondary Myelofibrosis; Unspecified Adult Solid Tumor, Protocol Specific
75 FR 5036 - Proposed Posting, Posting and Deposting of Stockyards
Federal Register 2010, 2011, 2012, 2013, 2014
2010-02-01
...The Grain Inspection, Packers and Stockyards Administration published a document in the Federal Register on July 6, 2004, concerning the proposed posting, posting and deposting of stockyards. The document shows the facility number for Shamrock Livestock Commission, Shamrock, Texas is the same as the facility number assigned to Texas Cattle Exchange, Inc., Eastland, Texas (TX-346).
Post-Traumatic Stress Disorder (PTSD)
... Information RePORT NIH Fact Sheets Home > Post-Traumatic Stress Disorder (PTSD) Small Text Medium Text Large Text Post-Traumatic Stress Disorder (PTSD) Post-traumatic stress disorder (PTSD) is ...
Koeslag, J H; Noakes, T D; Sloan, A W
1980-01-01
1. The effect of exercise on blood ketone body concentrations was studied in trained athletes and in sedentary subjects pedalling a bicycle ergometer. 2. Although the untrained subjects had higher heart rates and blood lactate concentrations at the same work load as the athletes, neither group developed ketonaemia even after intense or prolonged exercise. 3. Older subjects developed post-exercise ketonaemia, reaching maximum about 3 hr after exercise. 4. A high-carbohydrate diet before the exercise could prevent the onset of post-exercise ketonaemia and a low-carbohydrate diet enhanced it. The highest post-exercise blood ketone levels were recorded in marathon runners after a "glycogen-stripping' regimen. 5. Concentrations of free fatty acids, glucose, growth hormone and insulin in blood after exercise followed different patterns from that of ketones. 6. Post-exercise ketosis, when it occurs in untrained subjects, may be due to a lower carbohydrate intake than that of athletes. PMID:6997456
... gov Reason Number 87 to Get an HIV Test Veterans #DoingItMyWay – Testing for HIV June 27th is National HIV Testing Day Ryan White and HIV Testing Day 2018 Additional Resources AIDSInfo – Occupational Post-exposure Prophylaxis (PEP) Guidelines AIDSInfo – Nonoccupational Post-exposure ...
Sochan, Anne M
2011-07-01
How should nursing knowledge advance? This exploration contextualizes its evolution past and present. In addressing how it evolved in the past, a probable historical evolution of its development draws on the perspectives of Frank & Gills's World System Theory, Kuhn's treatise on Scientific Revolutions, and Foucault's notions of Discontinuities in scientific knowledge development. By describing plausible scenarios of how nursing knowledge evolved, I create a case for why nursing knowledge developers should adopt a post-structural stance in prioritizing their research agenda(s). Further, by adopting a post-structural stance, I create a case on how nurses can advance their disciplinary knowledge using an engaging post-colonial strategy. Given an interrupted history caused by influence(s) constraining nursing's knowledge development by power structures external, and internal, to nursing, knowledge development can evolve in the future by drawing on post-structural interpretation, and post-colonial strategy. The post-structural writings of Deleuze & Guattari's understanding of 'Nomadology' as a subtle means to resist being constrained by existing knowledge development structures, might be a useful stance to understanding the urgency of why nursing knowledge should advance addressing the structural influences on its development. Furthermore, Bhabha's post-colonial elucidation of 'Hybridity' as an equally discreet means to change the culture of those constraining structures is an appropriate strategy to enact how nursing knowledge developers can engage with existing power structures, and simultaneously influence that engagement. Taken together, 'post-structural stance' and 'post-colonial strategy' can refocus nursing scholarship to learn from its past, in order to develop relevant disciplinary knowledge in its future. © 2011 Blackwell Publishing Ltd.
Cytogenetic correlates of TET2 mutations in 199 patients with myeloproliferative neoplasms
Hussein, Kebede; Abdel-Wahab, Omar; Lasho, Terra L.; Van Dyke, Daniel L.; Levine, Ross L.; Hanson, Curtis A.; Pardanani, Animesh; Tefferi, Ayalew
2015-01-01
TET2 is a putative tumor suppressor gene located at chromosome 4q24. TET2 mutations were recently described in several myeloid neoplasms but correlations with cytogenetic findings have not been studied. Among a recently described cohort of patients with myeloproliferative neoplasms (MPN) who underwent TET2 mutation analysis, 199 had information on karyotype at diagnosis or time of TET2 testing: 71 polycythemia vera (PV), 55 primary myelofibrosis (PMF), 43 essential thrombocythemia (ET), 13 post-PV MF, 7 post-ET MF, and 10 blast phase MPN. Forty eight patients (24%) exhibited abnormal karyotype: 15 favorable (sole 20q-, 13q-, or +9), 8 unfavorable (complex karyotype or sole +8), and 25 “other” cytogenetic abnormalities. We found no significant difference either in the incidence or type of cytogenetic abnormalities between TET2 mutated (n = 25) and unmutated (n = 174) cases. Seventy nine patients, including 14 with TET2 mutations, underwent follow-up cytogenetic testing and the findings were again not affected by TET2 mutational status. We conclude that TET2 mutated MPN patients are not cytogenetically different than their TET2 unmutated counterparts. PMID:19957346
Treatment Options for Chronic Myeloproliferative Neoplasms
... are described below. Chronic myeloproliferative neoplasms sometimes become acute leukemia , in which too many abnormal white blood ... higher. Patients also have an increased risk of acute myeloid leukemia or primary myelofibrosis . Symptoms of polycythemia ...
Treatment Option Overview (Chronic Myeloproliferative Neoplasms)
... are described below. Chronic myeloproliferative neoplasms sometimes become acute leukemia , in which too many abnormal white blood ... higher. Patients also have an increased risk of acute myeloid leukemia or primary myelofibrosis . Symptoms of polycythemia ...
General Information about Chronic Myeloproliferative Neoplasms
... are described below. Chronic myeloproliferative neoplasms sometimes become acute leukemia , in which too many abnormal white blood ... higher. Patients also have an increased risk of acute myeloid leukemia or primary myelofibrosis . Symptoms of polycythemia ...
... are described below. Chronic myeloproliferative neoplasms sometimes become acute leukemia , in which too many abnormal white blood ... higher. Patients also have an increased risk of acute myeloid leukemia or primary myelofibrosis . Symptoms of polycythemia ...
Chronic Myeloproliferative Neoplasms Treatment
... are described below. Chronic myeloproliferative neoplasms sometimes become acute leukemia , in which too many abnormal white blood ... higher. Patients also have an increased risk of acute myeloid leukemia or primary myelofibrosis . Symptoms of polycythemia ...
... in which there is excessive breakdown of hemoglobin ( thalassemia ) The presence of cells called burr cells may ... shaped cells may indicate: Myelofibrosis Severe iron deficiency Thalassemia major Cancer in the bone marrow Anemia caused ...
... leukemia (cancer that starts in the bone marrow) Polycythemia vera (bone marrow disease that leads to an ... PA: Elsevier Saunders; 2013:chap 68. Tefferi A. Polycythemia vera, essential thrombocythemia, and primary myelofibrosis. In: Goldman ...
Post-mortem clinical pharmacology
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
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 established...
2018-03-13
Myelodysplastic Syndrome; Chronic Myelomonocytic Leukemia; Small Lymphocytic Lymphoma; Chronic Lymphocytic Leukemia; Prolymphocytic Leukemia; Chronic Myeloid Leukemia; Chronic Myeloproliferative Disorders; Multiple Myeloma; Plasma Cell Neoplasm; Plasma Cell Dyscrasia; Myelofibrosis; Polycythemia Vera; Essential Thrombocythemia; Plasma Cell Leukemia
Intra-Osseous Co-Transplant of UCB and hMSC
2018-02-27
Acute Lymphoblastic Leukemia; Acute Myelogenous Leukemia; Myelodysplastic Syndromes; Myelofibrosis; Relapsed Non-Hodgkin Lymphoma; Refractory Non-Hodgkin Lymphoma; Hodgkin Lymphoma; Refractory Hodgkin Lymphoma; Relapsed Chronic Lymphocytic Leukemia; Refractory Chronic Lymphocytic Leukemia; Lymphoid Malignancies; Chronic Myelogenous Leukemia
[The post-mortal right of privacy].
Jansen, Christoph
2008-01-01
Regarding the post-mortal right of privacy a distinction must be made between post-mortal protection of the personality, the post-mortal duty of confidentiality and the problems associated with the necessity to consent to a clinical post-mortem. The post-mortal protection of the personality both grants the post-mortal right to respect for privacy, which can be asserted by rights holder, and entitles to claim damages resulting from breach of any proprietary elements of the right to post-mortal privacy. The post-mortal duty of confidentiality protects against the unauthorized disclosure of confidential information about the patient even after his death. The physician has to decide whether the consent of the deceased may be presumed; however, he/she has to state the reasons why, due to medical confidentiality, he/she feels unable to disclose such information. Basically, the consent for clinical post-mortem can be effectively declared by way of a refusal clause in the hospital admission contract.
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…
Influence of post pattern and resin cement curing mode on the retention of glass fibre posts.
Poskus, L T; Sgura, R; Paragó, F E M; Silva, E M; Guimarães, J G A
2010-04-01
To evaluate the influence of post design and roughness and cement system (dual- or self-cured) on the retention of glass fibre posts. Two tapered and smooth posts (Exacto Cônico No. 2 and White Post No. 1) and two parallel-sided and serrated posts (Fibrekor 1.25 mm and Reforpost No. 2) were adhesively luted with two different resin cements--a dual-cured (Rely-X ARC) and a self-cured (Cement Post)--in 40 single-rooted teeth. The teeth were divided into eight experimental groups (n = 5): PFD--Parallel-serrated-Fibrekor/dual-cured; PRD--Parallel-serrated-Reforpost/dual-cured; TED--Tapered-smooth-Exacto Cônico/dual-cured; TWD--Tapered-smooth-White Post/dual-cured; PFS--Parallel-serrated-Fibrekor/self-cured; PRS--Parallel-serrated-Reforpost/self-cured; TES--Tapered-smooth-Exacto Cônico/self-cured; TWS--Tapered-smooth-White Post/self-cured. The specimens were submitted to a pull-out test at a crosshead speed of 0.5 mm min(-1). Data were analysed using analysis of variance and Bonferroni's multiple comparison test (alpha = 0.05). Pull-out results (MPa) were: PFD = 8.13 (+/-1.71); PRD = 8.30 (+/-0.46); TED = 8.68 (+/-1.71); TWD = 9.35 (+/-1.99); PFS = 8.54 (+/-2.23); PRS = 7.09 (+/-1.96); TES = 8.27 (+/-3.92); TWS = 7.57 (+/-2.35). No statistical significant difference was detected for posts and cement factors and their interaction. The retention of glass fibre posts was not affected by post design or surface roughness nor by resin cement-curing mode. These results imply that the choice for serrated posts and self-cured cements is not related to an improvement in retention.
[Fiber reinforced composite posts: literature review].
Frydman, G; Levatovsky, S; Pilo, R
2013-07-01
FRC (Fiber-reinforced composite) posts have been used since the beginning of the 90s with the introduction of carbon fiber posts. Fiber posts are widely used to restore endodontically treated teeth that have insufficient coronal tooth structure. Many in vitro and in vivo studies have shown the advantage of using FRC over prefabricated and cast metal post especially indicated in narrow root canals which are prone to vertically root fracture. The most frequent failure of FRC is debonding of a post at the resin cement/dentin interface. Bonding to dentin may be achieved by using etch-and-rinse and self-etch adhesives. The bond strength formed by self-adhesive cements is noticeably lower in comparison to the bond strength formed with resin cements applied in combination with etch-and-rinse adhesives. In an attempt to maximize resin bonding to fiber posts, several surface treatments have been suggested. Sandblasting with alumina particles results in an increased surface roughness and surface area without affecting the integrity of the post as long as it is applied by 50 microm alumina particles at 2.5 bars for maximally 5 seconds at a distance of 30 mm. The efficiency of post salinization is controversial and its contribution to the retention is of minor importance. Hydrofluoric acid has recently been proposed for etching glass fiber posts but this technique produced substantial damage to the glass fibers and affected the integrity of the post. Delayed cementation of fiber post (at least 24h post endodontic treatment) resulted in higher retentive strengths in comparison to immediate cementation and the best results were obtained when the luting agent was brought into the post space with lentulo spirals or specific syringes. The resin cement film thickness also influences the pullout strengths of fiber-reinforced posts .The highest bond strength values were obtained when the cement layer oversized the post spaces but not larger than 0.3 mm. The use of core build
In vitro evaluation of endodontic posts.
Drummond, J L
2000-05-01
To compare stainless steel posts and three different fibrous posts with respect to pullout (shear) strength from extracted third molars embedded in denture acrylic. Post space was prepared and the posts cemented with a resin cement according to manufacturer's instructions. Single step and multi-step dentin bonding systems were also evaluated. The testing was in tension at a loading rate of 2 mm/min. The statistical analysis indicated no significant difference in the pullout (shear) strength between any of the post groups tested. Also evaluated was the flexure strength of the fibrous posts before and after thermal cycling. Statistical analysis indicated a significant decrease in flexure strength for the respective fibrous posts following thermal cycling.
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.
Factors affecting the cement-post interface.
Zicari, F; De Munck, J; Scotti, R; Naert, I; Van Meerbeek, B
2012-03-01
To evaluate the effect of different factors on the push-out bond strength of glass fiber posts luted in simulated (standard) root canals using different composite cements. Three types of glass-fiber root-canal posts with a different matrix, namely an epoxy resin (RelyX post, 3M ESPE), a proprietary composite resin (FRC-Plus post, Ivoclar-Vivadent), and a methacrylate resin (GC post, GC), and three types of composite cements, namely an etch-and-rinse Bis-GMA-based (Variolink II, Ivoclar-Vivadent), a self-etch 10-MDP-based (Clearfil Esthetic Cement, Kuraray) and a self-adhesive (RelyX Unicem, 3M ESPE) cement, were tested. Posts were either left untreated (control), were treated with silane, or coated with silicated alumina particles (Cojet system, 3M ESPE). Posts were inserted up to 9-mm depth into composite CAD-CAM blocks (Paradigm, 3M ESPE) in order to solely test the strength of the cement-post interface, while excluding interference of the cement-dentin interface. After 1-week storage at 37 °C, three sections (coronal, middle, apical) of 2-mm thickness were subjected to a push-out bond-strength test. All three variables, namely the type of post, the composite cement and the post-surface pre-treatment, were found to significantly affect the push-out bond strength (p<0.001). Regarding the type of post, a significantly lower push-out bond strength was recorded for the FRC-Plus post (Ivoclar-Vivadent); regarding the composite cement, a significantly higher push-out bond strength was recorded for the self-adhesive cement Unicem (3M ESPE); and regarding the post-surface treatment, a significantly higher push-out bond strength was recorded when the post-surface was beforehand subjected to a Cojet (3M ESPE) combined sandblasting/silicatization surface pre-treatment. Many interactions between these three variables were found to be significant as well (p<0.001). Finally, the push-out bond strength was found to significantly reduce with depth from coronal to apical
Post-traumatic stress disorder
... medlineplus.gov/ency/article/000925.htm Post-traumatic stress disorder To use the sharing features on this page, please enable JavaScript. Post-traumatic stress disorder (PTSD) is a type of anxiety disorder . ...
[Post-mortem microbiology analysis].
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. Crown Copyright © 2012. Published by Elsevier Espana. All rights reserved.
Azacitidine and Sonidegib or Decitabine in Treating Patients With Myeloid Malignancies
2018-02-05
Chronic Myelomonocytic Leukemia; de Novo Myelodysplastic Syndrome; Essential Thrombocythemia; Myelodysplastic Syndrome; Myelodysplastic/Myeloproliferative Neoplasm; Polycythemia Vera; Previously Treated Myelodysplastic Syndrome; Primary Myelofibrosis; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia
2018-03-30
Acute Leukemia; Chronic Lymphocytic Leukemia; Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Diffuse Large B-Cell Lymphoma; Follicular Lymphoma; Graft Versus Host Disease; Mantle Cell Lymphoma; Marginal Zone Lymphoma; Myelodysplastic Syndrome; Myelofibrosis; Myeloproliferative Neoplasm; Small Lymphocytic Lymphoma
Code of Federal Regulations, 2011 CFR
2011-07-01
... 36 Parks, Forests, and Public Property 2 2011-07-01 2011-07-01 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...
Code of Federal Regulations, 2010 CFR
2010-07-01
... 36 Parks, Forests, and Public Property 2 2010-07-01 2010-07-01 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...
Code of Federal Regulations, 2014 CFR
2014-07-01
... 36 Parks, Forests, and Public Property 2 2014-07-01 2014-07-01 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...
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 of...
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...
Rigidity and retention of root canal posts.
Purton, D G; Chandler, N P; Love, R M
1998-03-28
To test the rigidity and the retention into roots of parallel root canal posts, one a spiral vented titanium post and the other a spiral serrated, hollow, stainless steel post. A serrated, stainless steel post was used as the control. A three-point bending test was used to test rigidity. To test retention, ten posts of each type were cemented into the roots of extracted teeth with a resin cement and the tensile loads required to remove them were compared using Student's t and Mann-Whitney U tests. The serrated stainless steel posts were significantly more rigid than either of the other types. The titanium posts and the stainless steel hollow posts were not significantly different in rigidity. The serrated, stainless steel posts were significantly better retained than either of the other types. The titanium posts showed greater retention than the hollow posts. Within the limits of the study the stainless steel, serrated posts were superior to the two newer types in terms of rigidity and retention into roots.
Atwood, Craig S; Hayashi, Kentaro; Meethal, Sivan Vadakkadath; Gonzales, Tina; Bowen, Richard L
2017-02-01
Post-reproductive lifespan varies greatly among species; human post-reproductive lifespan comprises ~30-50% of their total longevity, while semelparous salmon and dasyurid marsupials post-reproductive lifespan comprises <4% of their total longevity. To examine if the magnitude of hypothalamic-pituitary-gonadal (HPG) axis dyscrasia at the time of reproductive senescence determines post-reproductive lifespan, we examined the difference between pre- and post-reproductive (1) circulating sex hormones and (2) the ratio of sex steroids to gonadotropins (e.g., 17β-estradiol/follicle-stimulating hormone (FSH)), an index of the dysregulation of the HPG axis and the level of dyotic (death) signaling post-reproduction. Animals with a shorter post-reproductive lifespan (<4% total longevity) had a more marked decline in circulating sex steroids and corresponding elevation in gonadotropins compared to animals with a longer post-reproductive lifespan (30-60% total longevity). In semelparous female salmon of short post-reproductive lifespan (1%), these divergent changes in circulating hormone concentration post-reproduction equated to a 711-fold decrease in the ratio of 17β-estradiol/FSH between the reproductive and post-reproductive periods. In contrast, the decrease in the ratio of 17β-estradiol/FSH in iteroparous female mammals with long post-reproductive lifespan was significantly less (1.7-34-fold) post-reproduction. Likewise, in male semelparous salmon, the decrease in the ratio of testosterone/FSH (82-fold) was considerably larger than for iteroparous species (1.3-11-fold). These results suggest that (1) organisms with greater reproductive endocrine dyscrasia more rapidly undergo senescence and die, and (2) the contribution post-reproduction by non-gonadal (and perhaps gonadal) tissues to circulating sex hormones dictates post-reproductive tissue health and longevity. In this way, reproduction and longevity are coupled, with the degree of non-gonadal tissue hormone
External post-tensioning anchorage.
DOT National Transportation Integrated Search
2011-05-01
Post-tensioning tendons in segmental bridge construction are often only anchored within the deviator and pier segments. The effectiveness of the post-tensioning (PT) system is therefore dependent on proper functioning of the anchorages. On August 28,...
The role of JAK1/2 inhibitors in the treatment of chronic myeloproliferative neoplasms.
Keohane, Clodagh; Mesa, Ruben; Harrison, Claire
2013-01-01
In 2005, the description of the JAK2V617F mutation for the first time provided a molecular key to enable more rapid diagnosis and target for novel therapeutics in the myeloproliferative neoplasms. In 2007, the first-in-class agent INC18424, ruxolitinib, JAKafi, or JAKAVI was first tested in patients with intermediate-risk 2 or high-risk myelofibrosis regardless of whether they possessed the JAK2V617F mutation. Patients treated with this agent had major reduction in splenomegaly as well as impressive reduction, and in some cases resolution, of symptoms. This study was followed by the two Controlled Myelofibrosis Study with Oral JAK Inhibitor Therapy (COMFORT) trials (the first-ever phase III trials in myelofibrosis), which confirmed results in these aspects were superior to either placebo or standard care, and updated results show a survival advantage with this therapy. This paper discusses these results and data from other JAK inhibitors while speculating on the future of these therapies. It also reflects on the fact that the true targets and agents' mode of action are uncertain. Unlike targeted therapy for chronic myeloid leukemia (CML), these agents do not deliver molecular remission, and it is not clear whether their predominant benefit is mediated via JAK2, JAK1, or both. Nonetheless, the advent of the JAK inhibitor is a welcome advance and has made a dramatic improvement to the therapeutic landscape of these conditions.
[External post-mortem examination].
Hartwig, S
2016-09-01
The external post-mortem examination in Germany is a non-delegable medical duty for determination of death, identity of the deceased, cause of death, manner of death, time of death and notifiable infectious diseases. Within the framework of rescue service missions the physician is limited to ascertaining that death has occurred. The determination of death must be reliable and is automatically followed by a complete external post-mortem examination of the body, if necessary by another physician. The certain signs of death are livor mortis, rigor mortis and putrefaction. Reliable features for the occurrence of death are injuries which are not compatible with life and brain death. The external post-mortem examination is the basis for the decision on whether further criminal investigations are necessary. The external post-mortem examination and the accompanying death certification must always be meticulously carried out.
Russo, Maria Teresa; Di Stefano, Nicola
2014-01-01
The article calls into question the very possibility of a post-human aesthetics, starting from the following premise: rather than post-human, it is more correct to speak of post-natural, indicating by this expression a reality produced through a new type of evolution, which does not simply change human nature, but de-natures it, radically transforming it into an artefact. This post-nature which aspires to be perfect, immortal, invulnerable, is entirely devoid of beauty. In fact, while there may be an aesthetic of the artificial and of the artefact if it is in relation to objects, there is, however, no aesthetic of the post-human body. This is because is configured as a non-body and does not have the characteristics for what is commonly intended as beauty (harmony between matter and form, a reflection of inner life, uniqueness). Also in this case, it is more correct to speak of post-beauty, which in its properties appears to be the mirror image of beauty and ultimately, represents its complete dissolution.
Dietschi, Dider; Ardu, Stefano; Rossier-Gerber, Anne; Krejci, Ivo
2006-12-01
Fatigue resistance of post and cores is critical to the long term behavior of restored nonvital teeth. The purpose of this in vitro trial was to evaluate the influence of the post material's physical properties on the adaptation of adhesive post and core restorations after cyclic mechanical loading. Composite post and cores were made on endodontically treated deciduous bovine teeth using 3 anisotropic posts (made of carbon, quartz, or quartz-and-carbon fibers) and 3 isotropic posts (zirconium, stainless steel, titanium). Specimens were submitted to 3 successive loading phases--250,000 cycles at 50 N, 250,000 at 75 N, and 500,000 at 100 N--at a rate of 1.5 Hz. Restoration adaptation was evaluated under SEM, before and during loading (margins) and after test completion (margins and internal interfaces). Six additional samples were fabricated for the characterization of interface micromorphology using confocal microscopy. Mechanical loading increased the proportion of marginal gaps in all groups; carbon fiber posts presented the lowest final gap proportion (7.11%) compared to other stiffer metal-ceramic or softer fiber posts (11.0% to 19.1%). For internal adaptation, proportions of debonding between dentin and core or cement varied from 21.69% (carbon post) to 47.37% (stainless steel post). Debonding at the post-cement interface occurred only with isotropic materials. Confocal microscopy observation revealed that gaps were generally associated with an incomplete hybrid layer and reduced resin tags. Regardless of their rigidity, metal and ceramic isotropic posts proved less effective than fiber posts at stabilizing the post and core structure in the absence of the ferrule effect, due to the development of more interfacial defects with either composite or dentin.
14 CFR 417.415 - Post-launch and post-flight-attempt hazard controls.
Code of Federal Regulations, 2014 CFR
2014-01-01
... 14 Aeronautics and Space 4 2014-01-01 2014-01-01 false Post-launch and post-flight-attempt hazard controls. 417.415 Section 417.415 Aeronautics and Space COMMERCIAL SPACE TRANSPORTATION, FEDERAL AVIATION... evidence; and (4) Ensuring public safety from hazardous debris, such as plans for recovery and salvage of...
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... evidence; and (4) Ensuring public safety from hazardous debris, such as plans for recovery and salvage of...
14 CFR 417.415 - Post-launch and post-flight-attempt hazard controls.
Code of Federal Regulations, 2012 CFR
2012-01-01
... 14 Aeronautics and Space 4 2012-01-01 2012-01-01 false Post-launch and post-flight-attempt hazard controls. 417.415 Section 417.415 Aeronautics and Space COMMERCIAL SPACE TRANSPORTATION, FEDERAL AVIATION... evidence; and (4) Ensuring public safety from hazardous debris, such as plans for recovery and salvage of...
14 CFR 417.415 - Post-launch and post-flight-attempt hazard controls.
Code of Federal Regulations, 2010 CFR
2010-01-01
... 14 Aeronautics and Space 4 2010-01-01 2010-01-01 false Post-launch and post-flight-attempt hazard controls. 417.415 Section 417.415 Aeronautics and Space COMMERCIAL SPACE TRANSPORTATION, FEDERAL AVIATION... inadvertent liftoff. If an ignition signal has been sent to a solid rocket motor, the flight termination...
14 CFR 417.415 - Post-launch and post-flight-attempt hazard controls.
Code of Federal Regulations, 2011 CFR
2011-01-01
... 14 Aeronautics and Space 4 2011-01-01 2011-01-01 false Post-launch and post-flight-attempt hazard controls. 417.415 Section 417.415 Aeronautics and Space COMMERCIAL SPACE TRANSPORTATION, FEDERAL AVIATION... inadvertent liftoff. If an ignition signal has been sent to a solid rocket motor, the flight termination...
Code of Federal Regulations, 2010 CFR
2010-01-01
... 10 Energy 4 2010-01-01 2010-01-01 false Posting. 860.6 Section 860.6 Energy DEPARTMENT OF ENERGY TRESPASSING ON DEPARTMENT OF ENERGY PROPERTY § 860.6 Posting. Notices stating the pertinent prohibitions of §§ 860.3 and 860.4 and penalties of § 860.5 will be conspicuously posted at all entrances of each...
Code of Federal Regulations, 2011 CFR
2011-01-01
... 10 Energy 2 2011-01-01 2011-01-01 false Posting. 160.6 Section 160.6 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) TRESPASSING ON COMMISSION PROPERTY § 160.6 Posting. Notices stating the pertinent prohibitions of §§ 160.3 and 160.4 and penalties of § 160.5 will be conspicuously posted at all entrances of...
Code of Federal Regulations, 2012 CFR
2012-01-01
... 10 Energy 2 2012-01-01 2012-01-01 false Posting. 160.6 Section 160.6 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) TRESPASSING ON COMMISSION PROPERTY § 160.6 Posting. Notices stating the pertinent prohibitions of §§ 160.3 and 160.4 and penalties of § 160.5 will be conspicuously posted at all entrances of...
Code of Federal Regulations, 2010 CFR
2010-01-01
... 10 Energy 2 2010-01-01 2010-01-01 false Posting. 160.6 Section 160.6 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) TRESPASSING ON COMMISSION PROPERTY § 160.6 Posting. Notices stating the pertinent prohibitions of §§ 160.3 and 160.4 and penalties of § 160.5 will be conspicuously posted at all entrances of...
Code of Federal Regulations, 2011 CFR
2011-01-01
... 10 Energy 4 2011-01-01 2011-01-01 false Posting. 860.6 Section 860.6 Energy DEPARTMENT OF ENERGY TRESPASSING ON DEPARTMENT OF ENERGY PROPERTY § 860.6 Posting. Notices stating the pertinent prohibitions of §§ 860.3 and 860.4 and penalties of § 860.5 will be conspicuously posted at all entrances of each...
Code of Federal Regulations, 2014 CFR
2014-01-01
... 10 Energy 4 2014-01-01 2014-01-01 false Posting. 860.6 Section 860.6 Energy DEPARTMENT OF ENERGY TRESPASSING ON DEPARTMENT OF ENERGY PROPERTY § 860.6 Posting. Notices stating the pertinent prohibitions of §§ 860.3 and 860.4 and penalties of § 860.5 will be conspicuously posted at all entrances of each...
Code of Federal Regulations, 2012 CFR
2012-01-01
... 10 Energy 4 2012-01-01 2012-01-01 false Posting. 860.6 Section 860.6 Energy DEPARTMENT OF ENERGY TRESPASSING ON DEPARTMENT OF ENERGY PROPERTY § 860.6 Posting. Notices stating the pertinent prohibitions of §§ 860.3 and 860.4 and penalties of § 860.5 will be conspicuously posted at all entrances of each...
Code of Federal Regulations, 2013 CFR
2013-01-01
... 10 Energy 4 2013-01-01 2013-01-01 false Posting. 860.6 Section 860.6 Energy DEPARTMENT OF ENERGY TRESPASSING ON DEPARTMENT OF ENERGY PROPERTY § 860.6 Posting. Notices stating the pertinent prohibitions of §§ 860.3 and 860.4 and penalties of § 860.5 will be conspicuously posted at all entrances of each...
Code of Federal Regulations, 2013 CFR
2013-01-01
... 10 Energy 2 2013-01-01 2013-01-01 false Posting. 160.6 Section 160.6 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) TRESPASSING ON COMMISSION PROPERTY § 160.6 Posting. Notices stating the pertinent prohibitions of §§ 160.3 and 160.4 and penalties of § 160.5 will be conspicuously posted at all entrances of...
Code of Federal Regulations, 2014 CFR
2014-01-01
... 10 Energy 2 2014-01-01 2014-01-01 false Posting. 160.6 Section 160.6 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) TRESPASSING ON COMMISSION PROPERTY § 160.6 Posting. Notices stating the pertinent prohibitions of §§ 160.3 and 160.4 and penalties of § 160.5 will be conspicuously posted at all entrances of...
Clinical evaluation of fiber-reinforced epoxy resin posts and cast post and cores.
Ferrari, M; Vichi, A; García-Godoy, F
2000-05-01
This retrospective study evaluated treatment outcome of cast post and core and Composipost systems after 4 yrs of clinical service. 200 patients were included in the study. They were divided in two groups of 100 endodontically treated teeth restored with a post. Group 1: Composipost systems were luted into root canal following the manufacturer's instructions. Group 2: Cast post and cores were cemented into root canal preparations with a traditional technique. The patients were recalled after 6 months, 1, 2 and 4 yrs and clinical and radiographic examinations were completed. Endodontic and prosthodontic results were recorded. Group 1: 95% of the teeth restored with Composiposts showed clinical success; 3% of these samples were excluded for noncompliance and 2% showed endodontic failure. Group 2: Clinical success was found with 84% of teeth restored with cast post and core. 2% of these samples were excluded for noncompliance, 9% showed root fracture, 2% dislodgment of crown and 3% endodontic failure. Statistical evaluation showed significant differences between Groups 1 and 2 (P < 0.001). The results of this retrospective study indicated that the Composipost system was superior to the conventional cast post and core system after 4 yrs of clinical service.
2018-06-22
Acute Myeloid Leukemia; Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Chronic Myelomonocytic Leukemia; Essential Thrombocythemia; Myelodysplastic/Myeloproliferative Neoplasm; Myelofibrosis; Polycythemia Vera; Recurrent Adult Acute Myeloid Leukemia; Refractory Acute Myeloid Leukemia
2014-12-16
Accelerated Phase Chronic Myelogenous Leukemia; Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Blastic Phase Chronic Myelogenous Leukemia; Chronic Eosinophilic Leukemia; Chronic Myelomonocytic Leukemia; Essential Thrombocythemia; Philadelphia Chromosome Negative Chronic Myelogenous Leukemia; Polycythemia Vera; Primary Myelofibrosis; Relapsing Chronic Myelogenous Leukemia
ERIC Educational Resources Information Center
Turton, Roger
2016-01-01
"Mathematical Lens" uses photographs as a springboard for mathematical inquiry and appears in every issue of "Mathematics Teacher." Recently while dismantling an old wooden post-and-rail fence, Roger Turton noticed something very interesting when he piled up the posts and rails together in the shape of a prism. The total number…
Lee, Byung Kook; Song, Kyoung Hwan; Jung, Yong Hun; Lee, Dong Hun; Youn, Chun Sung; Lee, Sung Min; Cho, Yong Soo; Jeung, Kyung Woon
2015-12-01
We evaluated the influence of post-rewarming temperature management (PRTM) on post-rewarming fever development and determined the association between the temperature in the immediate post-targeted temperature management (TTM) period and outcomes. This retrospective observational study included consecutive adult cardiac arrest survivors treated with TTM from January 2008 to December 2013. Beginning in August 2010, our institution implemented a PRTM protocol involving continued use of temperature management device to maintain normothermia during the first 24h after rewarming. The outcomes were in-hospital mortality and neurologic outcome at discharge. We evaluated the effect on clinical outcomes of post-rewarming fever defined at a temperature over 38 °C within 48 h after rewarming. Of 277 included patients, 55.2% underwent PRTM. The incidence of post-rewarming fever did not differ between the PRTM and no-PRTM groups (odds ratio [OR] 0.963, confidence interval [CI] 0.519, 1.787). Post-rewarming fever was associated with decreased in-hospital mortality (OR 0.243, CI 0.110, 0.534) and decreased rate of unfavorable neurologic outcome (OR 0.312, CI 0.182, 0.534). During 48 h following rewarming, mean temperature was 36.5 °C (36.2-36.8 °C), and peak temperature was 37.5 °C (36.8-38.1 °C). On multivariate analyses, lower mean temperature was associated with increased in-hospital mortality (OR 0.099, CI 0.037, 0.262) and unfavorable neurologic outcome (OR 0.071, CI 0.026, 0.193). It appeared that PRTM did not prevent post-rewarming fever development. Post-rewarming fever was associated with favorable outcomes while lower body temperature after rewarming was associated with unfavorable outcomes. Our results require further confirmation by larger prospective studies. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
76 FR 64134 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-10-17
... POSTAL REGULATORY COMMISSION [Docket No. A2012-5; Order No. 901] Post Office Closing AGENCY... the closing of the Conception Junction, Missouri post office has been filed. It identifies preliminary... Postal Service's determination to close the Conception Junction post office in Conception Junction...
76 FR 73742 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-11-29
... POSTAL REGULATORY COMMISSION [Docket No. A2012-54; Order No. 988] Post Office Closing AGENCY... the consolidation of the Slayden, Tennessee post office has been filed. It identifies preliminary... Postal Service's determination to consolidate the Slayden post office in Slayden, Tennessee. The petition...
Embedding Fonts in MetaPost Output
2016-04-19
by John Hobby ) based on Donald Knuth’s META- FONT [4] with high quality PostScript output. An outstanding feature of MetaPost is that typeset fonts in...output, the graphics are perfectly scalable to any arbitrary res- olution. John Hobby , its author, writes: “[MetaPost] is really a programming lan- guage...for generating graphics, especially fig- ures for TEX [5] and troff documents.” This quote by Hobby indicates that MetaPost figures are not only
Sarangi, Susmita; Lanikova, Lucie; Kapralova, Katarina; Acharya, Suchitra; Swierczek, Sabina; Lipton, Jeffrey M; Wolfe, Lawrence; Prchal, Josef T
2014-11-01
von Hippel-Lindau (VHL) protein is the principal negative regulator of hypoxia sensing mediated by transcription factors. Mutations in exon 3 of the VHL gene lead to Chuvash (VHL(R200W)) and Croatian (VHL(H191D)) polycythemias. Here, we describe an infant of Bangladesh ethnicity with a novel homozygous VHL(D126N) mutation with congenital polycythemia and dramatically elevated erythropoietin (EPO) levels, who developed severe fatal pulmonary hypertension. In contrast to Chuvash polycythemia, erythroid progenitors (BFU-Es) did not reveal a marked EPO hypersensitivity. Further, NF-E2 and RUNX1 transcripts that correlate with BFU-Es EPO hypersensitivity in polycythemic mutations were not elevated. © 2014 Wiley Periodicals, Inc.
10 CFR 20.1902 - Posting requirements.
Code of Federal Regulations, 2011 CFR
2011-01-01
... NUCLEAR REGULATORY COMMISSION STANDARDS FOR PROTECTION AGAINST RADIATION Precautionary Procedures § 20.1902 Posting requirements. (a) Posting of radiation areas. The licensee shall post each radiation area with a conspicuous sign or signs bearing the radiation symbol and the words “CAUTION, RADIATION AREA...
10 CFR 20.1902 - Posting requirements.
Code of Federal Regulations, 2013 CFR
2013-01-01
... NUCLEAR REGULATORY COMMISSION STANDARDS FOR PROTECTION AGAINST RADIATION Precautionary Procedures § 20.1902 Posting requirements. (a) Posting of radiation areas. The licensee shall post each radiation area with a conspicuous sign or signs bearing the radiation symbol and the words “CAUTION, RADIATION AREA...
10 CFR 20.1902 - Posting requirements.
Code of Federal Regulations, 2010 CFR
2010-01-01
... NUCLEAR REGULATORY COMMISSION STANDARDS FOR PROTECTION AGAINST RADIATION Precautionary Procedures § 20.1902 Posting requirements. (a) Posting of radiation areas. The licensee shall post each radiation area with a conspicuous sign or signs bearing the radiation symbol and the words “CAUTION, RADIATION AREA...
10 CFR 20.1902 - Posting requirements.
Code of Federal Regulations, 2014 CFR
2014-01-01
... NUCLEAR REGULATORY COMMISSION STANDARDS FOR PROTECTION AGAINST RADIATION Precautionary Procedures § 20.1902 Posting requirements. (a) Posting of radiation areas. The licensee shall post each radiation area with a conspicuous sign or signs bearing the radiation symbol and the words “CAUTION, RADIATION AREA...
10 CFR 20.1902 - Posting requirements.
Code of Federal Regulations, 2012 CFR
2012-01-01
... NUCLEAR REGULATORY COMMISSION STANDARDS FOR PROTECTION AGAINST RADIATION Precautionary Procedures § 20.1902 Posting requirements. (a) Posting of radiation areas. The licensee shall post each radiation area with a conspicuous sign or signs bearing the radiation symbol and the words “CAUTION, RADIATION AREA...
76 FR 11824 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-03-03
... POSTAL REGULATORY COMMISSION [Docket No. A2011-9; Order No. 682] Post Office Closing AGENCY... the closing of the Mitchellville Post Office in Mitchellville, Tennessee has been filed. It identifies... Mitchellville post office in Mitchellville, Tennessee. The petition, which was filed by Larry D. Draper...
76 FR 55951 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-09-09
... POSTAL REGULATORY COMMISSION [Docket No. A2011-58; Order No. 838] Post Office Closing AGENCY... the closing of the Bentonville, Ohio post office has been filed. It identifies preliminary steps and... Postal Service's determination to close the Bentonville post office in Bentonville, Ohio. The petition...
76 FR 64131 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-10-17
... POSTAL REGULATORY COMMISSION [Docket No. A2012-2; Order No. 898] Post Office Closing AGENCY... the closing of the Bloomington, Idaho post office has been filed. It identifies preliminary steps and... Postal Service's determination to close the Bloomington post office in Bloomington, Idaho. The petitions...
76 FR 67768 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-11-02
... POSTAL REGULATORY COMMISSION [Docket No. A2012-22; Order No. 926] Post Office Closing AGENCY... the closing of the Sattley/Calpine, California post office has been filed. It identifies preliminary... Postal Service's determination to close the Sattley/Calpine post office in Calpine, California. The...
76 FR 67000 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-10-28
... POSTAL REGULATORY COMMISSION [Docket No. A2012-15; Order No. 916] Post Office Closing AGENCY... the closing of the Jenkinjones, West Virginia post office has been filed. It identifies preliminary... Postal Service's determination to close the Jenkinjones post office in Jenkinjones, West Virginia. The...
75 FR 54192 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2010-09-03
... POSTAL REGULATORY COMMISSION [Docket No. A2010-5; Order No. 526] Post Office Closing AGENCY... the closing of the Rentiesville Post Office, Rentiesville, Oklahoma 74459 has been filed. It... Rentiesville Post Office, Rentiesville, Oklahoma 74459. The appeal, postmarked August 23, 2010, was received by...
76 FR 69771 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-11-09
... POSTAL REGULATORY COMMISSION [Docket No. A2012-39; Order No. 945] Post Office Closing AGENCY... the closing of the Kettlersville, Ohio post office has been filed. It identifies preliminary steps and... Postal Service's determination to close the Kettlersville post office in Kettlersville, Ohio. The...
76 FR 68516 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-11-04
... POSTAL REGULATORY COMMISSION [Docket No. A2012-33; Order No. 939] Post Office Closing AGENCY... the closing of the Woodstock, Minnesota post office has been filed. It identifies preliminary steps... Postal Service's determination to close the Woodstock post office in Woodstock, Minnesota. The first...
76 FR 72727 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-11-25
... POSTAL REGULATORY COMMISSION [Docket No. A2012-51; Order No. 980] Post Office Closing AGENCY... the closing of the Lafayette, Kentucky post office has been filed. It identifies preliminary steps and... Postal Service's determination to close the Lafayette post office in Lafayette, Kentucky. The petition...
76 FR 60947 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-09-30
... POSTAL REGULATORY COMMISSION [Docket No. A2011-84; Order No. 874] Post Office Closing AGENCY... the closing of the Jordanville, New York post office has been filed. It identifies preliminary steps... Postal Service's determination to close the Jordanville post office in Jordanville, New York. The...
76 FR 60562 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-09-29
... POSTAL REGULATORY COMMISSION [Docket No. A2011-80; Order No. 869] Post Office Closing AGENCY... the closing of the Tarrifville, Connecticut post office has been filed. It identifies preliminary... determination to close the Tariffville post office in Tariffville, Connecticut. The first petition was filed by...
Evaluation of Salivary Flow Rate, pH and Buffer in Pre, Post & Post Menopausal Women on HRT
D.R., Mahesh; G., Komali; K., Jayanthi; D., Dinesh; T.V., Saikavitha; Dinesh, Preeti
2014-01-01
Background: Climateric is considered to be a natural phase of life which by definition is the period of life starting from decline in ovarian activity until after the end of ovarian function. It is accompanied by various health consequences that include the changes in saliva too. This study was carried out to evaluate the salivary flow rate, pH, buffering capacity in pre-menopausal, post-menopausal and post-menopausal women on HRT. Aims and objectives: (1) To evaluate the salivary flow rate, pH of resting saliva and stimulated saliva and buffer capacity of stimulated saliva in pre-menopausal, post-menopausal and post-menopausal women on Hormone Replacement Therapy (HRT). (2) To compare the above salivary findings between pre-menopausal, post-menopausal and post-menopausal women on HRT. Materials and Methods: The study was carried out on 60 patients. These patients were divided into three groups of 20 patients: Group 1: Pre-menopausal women (control), Group 2: post-menopausal women (case), Group 3: post-menopausal women on HRT (case). The control group consisted of 20 women volunteers, having regular ovulatory menstrual cycles with no known systemic illness and deleterious habits and Group 2 consists of 20 post-menopausal women and Group 3 will consist of 20 post-menopausal women on HRT. After clearing the mouth by swallowing, stimulated saliva was collected after chewing paraffin for 10 mins in to a glass centrifuge tube graded in 0.1 mL increments up to 10mL.in rare cases the collection time will be reduced or extended (5-15 min), salivary flow rate will be determined as ml/min, immediately after collection, pH was determined by dipping pH test paper directly into the sample of oral fluid, salivary buffer capacity was determined by using saliva check buffer kit (GC corporation). The data obtained was statistically evaluated using chi-square test, fisher exact test ANOVA analysis. Results: In our study we found salivary flow rate significantly lower in the post
Evaluation of Salivary Flow Rate, pH and Buffer in Pre, Post & Post Menopausal Women on HRT.
D R, Mahesh; G, Komali; K, Jayanthi; D, Dinesh; T V, Saikavitha; Dinesh, Preeti
2014-02-01
Climateric is considered to be a natural phase of life which by definition is the period of life starting from decline in ovarian activity until after the end of ovarian function. It is accompanied by various health consequences that include the changes in saliva too. This study was carried out to evaluate the salivary flow rate, pH, buffering capacity in pre-menopausal, post-menopausal and post-menopausal women on HRT. (1) To evaluate the salivary flow rate, pH of resting saliva and stimulated saliva and buffer capacity of stimulated saliva in pre-menopausal, post-menopausal and post-menopausal women on Hormone Replacement Therapy (HRT). (2) To compare the above salivary findings between pre-menopausal, post-menopausal and post-menopausal women on HRT. The study was carried out on 60 patients. These patients were divided into three groups of 20 patients: Group 1: Pre-menopausal women (control), Group 2: post-menopausal women (case), Group 3: post-menopausal women on HRT (case). The control group consisted of 20 women volunteers, having regular ovulatory menstrual cycles with no known systemic illness and deleterious habits and Group 2 consists of 20 post-menopausal women and Group 3 will consist of 20 post-menopausal women on HRT. After clearing the mouth by swallowing, stimulated saliva was collected after chewing paraffin for 10 mins in to a glass centrifuge tube graded in 0.1 mL increments up to 10mL.in rare cases the collection time will be reduced or extended (5-15 min), salivary flow rate will be determined as ml/min, immediately after collection, pH was determined by dipping pH test paper directly into the sample of oral fluid, salivary buffer capacity was determined by using saliva check buffer kit (GC corporation). The data obtained was statistically evaluated using chi-square test, fisher exact test ANOVA analysis. In our study we found salivary flow rate significantly lower in the post-menopausal women in comparison with the menstruating women and also
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.
ERIC Educational Resources Information Center
Onwuegbuzie, Anthony J.
Since the latter part of the 19th century, a fervent debate has ensued about quantitative and qualitative research paradigms. From these disputes, purists have emerged on both sides. Quantitative purists express assumptions that are consistent with a positivist philosophy, whereas qualitative purists (i.e., post-positivists, post-structuralists,…
Quick response airborne command post communications
NASA Astrophysics Data System (ADS)
Blaisdell, Randy L.
1988-08-01
National emergencies and strategic crises come in all forms and sizes ranging from natural disasters at one end of the scale up to and including global nuclear warfare at the other. Since the early 1960s the U.S. Government has spent billions of dollars fielding airborne command posts to ensure continuity of government and the command and control function during times of theater conventional, theater nuclear, and global nuclear warfare. Unfortunately, cost has prevented the extension of the airborne command post technology developed for these relatively unlikely events to the lower level, though much more likely to occur, crises such as natural disasters, terrorist acts, political insurgencies, etc. This thesis proposes the implementation of an economical airborne command post concept to address the wide variety of crises ignored by existing military airborne command posts. The system is known as the Quick Response Airborne Command Post (QRAC Post) and is based on the exclusive use of commercially owned and operated aircraft, and commercially available automated data processing and communications resources. The thesis addresses the QRAC Post concept at a systems level and is primarily intended to demonstrate how current technology can be exploited to economically achieve a national objective.
76 FR 71083 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-11-16
... POSTAL REGULATORY COMMISSION [Docket No. A2012-43; Order No. 960] Post Office Closing AGENCY... the closing of the Andover, Illinois post office has been filed. It identifies preliminary steps and... Postal Service's determination to close the Andover post office in Andover, Illinois. The petition for...
77 FR 1751 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2012-01-11
... POSTAL REGULATORY COMMISSION [Docket No. A2012-95; Order No. 1083] Post Office Closing AGENCY... the closing of the Strandquist, Minnesota post office has been filed. It identifies preliminary steps... close the Strandquist post office in Strandquist, Minnesota. The petition for review was filed by Eunice...
77 FR 4377 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2012-01-27
... POSTAL REGULATORY COMMISSION [Docket No. A2012-111; Order No. 1154] Post Office Closing AGENCY... the closing of the Randolph, Iowa post office has been filed. It identifies preliminary steps and... petition for review of the Postal Service's determination to close the Randolph post office in Randolph...
76 FR 67773 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-11-02
... POSTAL REGULATORY COMMISSION [Docket No. A2012-24; Order No. 928] Post Office Closing AGENCY... the closing of the Ozan, Arkansas post office has been filed. It identifies preliminary steps and... Postal Service's determination to close the Ozan post office in Ozan, Arkansas. The petition for review...
76 FR 64130 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-10-17
... POSTAL REGULATORY COMMISSION [Docket No. A2012-3; Order No. 899] Post Office Closing AGENCY... the closing of the Scott, Mississippi post office has been filed. It identifies preliminary steps and... Postal Service's determination to close the Scott post office in Scott, Mississippi. The petition for...
76 FR 71084 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-11-16
... POSTAL REGULATORY COMMISSION [Docket No. A2012-45; Order No. 962] Post Office Closing AGENCY... the closing of the Orchard, Iowa post office has been filed. It identifies preliminary steps and... Postal Service's determination to close the Orchard post office in Orchard, Iowa. The first petition for...
76 FR 78320 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-12-16
... POSTAL REGULATORY COMMISSION [Docket No. A2012-82; Order No. 1031] Post Office Closing AGENCY... the closing of the South Greenfield, Missouri post office has been filed. It identifies preliminary... post office in South Greenfield, Missouri. The petition for review was filed by Kitty Ayres (Petitioner...
76 FR 73743 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-11-29
... POSTAL REGULATORY COMMISSION [Docket No. A2012-55; Order No. 989] Post Office Closing AGENCY... the closing of the Nemaha, Nebraska post office has been filed. It identifies preliminary steps and... Postal Service's determination to close the Nemaha post office in Nemaha, Nebraska. The petition for...
76 FR 64129 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-10-17
... POSTAL REGULATORY COMMISSION [Docket No. A2012-4; Order No. 900] Post Office Closing AGENCY... the closing of the Balm, Florida post office has been filed. It identifies preliminary steps and... Postal Service's determination to close the Balm post office in Balm, Florida. The petition for review...
76 FR 82003 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-12-29
... POSTAL REGULATORY COMMISSION [Docket No. A2012-91; Order No. 1064] Post Office Closing AGENCY... the closing of the Fostoria, Iowa post office has been filed. It identifies preliminary steps and... five petitions for review of the Postal Service's determination to close the Fostoria post office in...
76 FR 67002 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-10-28
... POSTAL REGULATORY COMMISSION [Docket No. A2012-13; Order No. 914] Post Office Closing AGENCY... the closing of the New Hampton, Missouri post office has been filed. It identifies preliminary steps... Postal Service's determination to close the New Hampton post office in New Hampton, Missouri. The...
76 FR 73745 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-11-29
... POSTAL REGULATORY COMMISSION [Docket No. A2012-58; Order No. 992] Post Office Closing AGENCY... the closing of the Deering, Missouri post office has been filed. It identifies preliminary steps and... Postal Service's determination to close the Deering post office in Deering, Missouri. The petition for...
76 FR 28103 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-05-13
... POSTAL REGULATORY COMMISSION [Docket No. A2011-15; Order No. 726] Post Office Closing AGENCY... the closing of the Gywnedd, Pennsylvania post office has been filed. It identifies preliminary steps..., Pennsylvania post office. The petition, which was filed by Christina Surowiec (Petitioner), is postmarked May 2...
76 FR 76202 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-12-06
... POSTAL REGULATORY COMMISSION [Docket No. A2012-64; Order No. 1006] Post Office Closing AGENCY... the closing of the Little America, Wyoming post office has been filed. It identifies preliminary steps... for review of the Postal Service's determination to close the Little America post office in Little...
77 FR 4383 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2012-01-27
... POSTAL REGULATORY COMMISSION [Docket No. A2012-112; Order No. 1155] Post Office Closing AGENCY... the closing of the Elwell, Michigan post office has been filed. It identifies preliminary steps and... three petitions for review of the Postal Service's determination to close the Elwell post office in...
76 FR 78319 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-12-16
... POSTAL REGULATORY COMMISSION [Docket No. A2012-81; Order No. 1030] Post Office Closing AGENCY... the closing of the Phippsburg, Colorado post office has been filed. It identifies preliminary steps... petitions for review of the Postal Service's determination to close the Phippsburg post office in Phippsburg...
76 FR 70175 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-11-10
... POSTAL REGULATORY COMMISSION [Docket No. A2012-38; Order No. 944] Post Office Closing AGENCY... the closing of the New Boston, Illinois post office has been filed. It identifies preliminary steps... Postal Service's determination to close the New Boston post office in New Boston, Illinois. The first...
76 FR 65545 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-10-21
... POSTAL REGULATORY COMMISSION [Docket No. A2012-10; Order No. 908] Post Office Closing AGENCY... the closing of the Agate, Colorado post office has been filed. It identifies preliminary steps and... Postal Service's determination to close the Agate post office in Agate, Colorado. The petition for review...
77 FR 4379 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2012-01-27
... POSTAL REGULATORY COMMISSION [Docket No. A2012-115; Order No. 1158] Post Office Closing AGENCY... the closing of the Highfalls, North Carolina post office has been filed. It identifies preliminary... petition for review of the Postal Service's determination to close the Highfalls post office in Highfalls...
76 FR 75569 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-12-02
... POSTAL REGULATORY COMMISSION [Docket No. A2012-60; Order No. 1001] Post Office Closing AGENCY... the closing of the Prescott, Iowa post office has been filed. It identifies preliminary steps and... determination to close the Prescott post office in Prescott, Iowa. The first petition for review received...
76 FR 64133 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-10-17
... POSTAL REGULATORY COMMISSION [Docket No. A2012-7; Order No. 904] Post Office Closing AGENCY... the closing of the Campaign, Tennessee post office has been filed. It identifies preliminary steps and... Postal Service's determination to close the Campaign post office in Campaign, Tennessee. The petition for...
77 FR 3809 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2012-01-25
... POSTAL REGULATORY COMMISSION [Docket No. A2012-106; Order No. 1145] Post Office Closing AGENCY... the closing of the Pierceville, Indiana post office has been filed. It identifies preliminary steps... three petitions for review of the Postal Service's determination to close the Pierceville post office in...
77 FR 5064 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2012-02-01
... POSTAL REGULATORY COMMISSION [Docket No. A2012-116; Order No. 1175] Post Office Closing AGENCY... the closing of the Imperial, Texas post office has been filed. It identifies preliminary steps and... four petitions for review of the Postal Service's determination to close the Imperial post office in...
76 FR 61405 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-10-04
... POSTAL REGULATORY COMMISSION [Docket No. A2011-87; Order No. 879] Post Office Closing AGENCY... the closing of the Pomfret Center, Connecticut post office has been filed. It identifies preliminary... determination to close the Pomfret Center post office in Pomfret Center, Connecticut. The petition was filed by...
76 FR 75917 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-12-05
... POSTAL REGULATORY COMMISSION [Docket No. A2012-63; Order No. 1004] Post Office Closing AGENCY... the closing of the Fort Meade, South Dakota post office has been filed. It identifies preliminary... Postal Service's determination to close the Fort Meade post office in Fort Meade, South Dakota. The...
76 FR 67498 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-11-01
... POSTAL REGULATORY COMMISSION [Docket No. A2012-17; Order No. 918] Post Office Closing AGENCY... the closing of the Venice, California post office has been filed. It identifies preliminary steps and... application for suspension of the Postal Service's determination to close the Venice post office in Venice...
76 FR 67770 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-11-02
... POSTAL REGULATORY COMMISSION [Docket No. A2012-23; Order No. 927] Post Office Closing AGENCY... the closing of the Fairfield, Kentucky post office has been filed. It identifies preliminary steps and... application for suspension of the Postal Service's determination to close the Fairfield post office in...
76 FR 73746 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-11-29
... POSTAL REGULATORY COMMISSION [Docket No. A2012-56; Order No. 990] Post Office Closing AGENCY... the closing of the Rippey, Iowa post office has been filed. It identifies preliminary steps and... review of the Postal Service's determination to close the Rippey post office in Rippey, Iowa. The...
76 FR 55952 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-09-09
... POSTAL REGULATORY COMMISSION [Docket No. A2011-59; Order No. 839] Post Office Closing AGENCY... the closing of the Velpen, Indiana post office has been filed. It identifies preliminary steps and... Postal Service's determination to close the Velpen post office in Velpen, Indiana. The petition was filed...
76 FR 67766 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-11-02
... POSTAL REGULATORY COMMISSION [Docket No. A2012-21; Order No. 925] Post Office Closing AGENCY... the closing of the Saratoga, Arkansas post office has been filed. It identifies preliminary steps and... Postal Service's determination to close the Saratoga post office in Saratoga, Arkansas. The petition for...
76 FR 67767 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-11-02
... POSTAL REGULATORY COMMISSION [Docket No. A2012-25; Order No. 929] Post Office Closing AGENCY... the closing of the Glenwood, Alabama post office has been filed. It identifies preliminary steps and... Postal Service's determination to close the Glenwood post office in Glenwood, Alabama. The petition for...
76 FR 19149 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-04-06
... POSTAL REGULATORY COMMISSION [Docket No. A2011-12; Order No. 707] Post Office Closing AGENCY... the closing of the Wesleyville Post Office in Wesleyville, Pennsylvania has been filed. It identifies... determination to close the Wesleyville, Pennsylvania post office. The petition was filed online by William A...
76 FR 67001 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-10-28
... POSTAL REGULATORY COMMISSION [Docket No. A2012-14; Order No. 915] Post Office Closing AGENCY... the closing of the Witter, Arkansas post office has been filed. It identifies preliminary steps and... Postal Service's determination to close the Witter post office in Witter, Arkansas. The petition for...
76 FR 75918 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-12-05
... POSTAL REGULATORY COMMISSION [Docket No. A2012-62; Order No. 1003] Post Office Closing AGENCY... the closing of the Lanagan, Missouri post office has been filed. It identifies preliminary steps and... Postal Service's determination to close the Lanagan post office in Lanagan, Missouri. The petition for...
76 FR 44054 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-07-22
... POSTAL REGULATORY COMMISSION [Docket No. A2011-21; Order No. 761] Post Office Closing AGENCY... the closing of the Ukiah, California Main Post Office has been filed. It identifies preliminary steps... Office, Ukiah, California. The petition, which was filed by the Save Ukiah Post Office Committee and...
76 FR 70174 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-11-10
... POSTAL REGULATORY COMMISSION [Docket No. A2012-42; Order No. 949] Post Office Closing AGENCY... the closing of the Amoret, Missouri post office has been filed. It identifies preliminary steps and... Postal Service's determination to close the Amoret post office in Amoret, Missouri. The petition for...
77 FR 4381 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2012-01-27
... POSTAL REGULATORY COMMISSION [Docket No. A2012-113; Order No. 1156] Post Office Closing AGENCY... the closing of the Peterson, Minnesota post office has been filed. It identifies preliminary steps and... petition for review of the Postal Service's determination to close the Peterson post office in Peterson...
76 FR 67003 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-10-28
... POSTAL REGULATORY COMMISSION [Docket No. A2012-16; Order No. 917] Post Office Closing AGENCY... the closing of the Adona, Arkansas post office has been filed. It identifies preliminary steps and... Postal Service's determination to close the Adona post office in Adona, Arkansas. The petition for review...
76 FR 75916 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-12-05
... POSTAL REGULATORY COMMISSION [Docket No. A2012-61; Order No. 1002] Post Office Closing AGENCY... the closing of the Prince, West Virginia post office has been filed. It identifies preliminary steps... Postal Service's determination to close the Prince post office in Prince, West Virginia. The petition for...
76 FR 45882 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-08-01
... POSTAL REGULATORY COMMISSION [Docket No. A2011-28; Order No. 771] Post Office Closing AGENCY... the closing of the Goodwin, Arkansas post office has been filed. It identifies preliminary steps and... to close the post office in Goodwin, Arkansas. The petition was filed by Randy Jones (Petitioner...
77 FR 1963 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2012-01-12
... POSTAL REGULATORY COMMISSION [Docket No. A2012-101; Order No. 1102] Post Office Closing AGENCY... the closing of the Cardwell, Montana post office has been filed. It identifies preliminary steps and... petitions for review of the Postal Service's determination to close the Cardwell post office in Cardwell...
76 FR 51436 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-08-18
... POSTAL REGULATORY COMMISSION [Docket No. A2011-45; Order No. 801] Post Office Closing AGENCY... the closing of the Sublime, Texas post office has been filed. It identifies preliminary steps and... Postal Service's determination to close the post office in Sublime, Texas. The petition was filed by...
77 FR 1959 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2012-01-12
... POSTAL REGULATORY COMMISSION [Docket No. A2012-102; Order No. 1103] Post Office Closing AGENCY... the closing of the Parlin, Colorado post office has been filed. It identifies preliminary steps and... for review of the Postal Service's determination to close the Parlin post office in Parlin, Colorado...
76 FR 69770 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-11-09
... POSTAL REGULATORY COMMISSION [Docket No. A2012-37; Order No. 943] Post Office Closing AGENCY... the closing of the Boles, Arkansas post office has been filed. It identifies preliminary steps and... review of the Postal Service's determination to close the Boles post office in Boles, Arkansas. The...
76 FR 77026 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-12-09
... POSTAL REGULATORY COMMISSION [Docket No. A2012-77; Order No. 1020] Post Office Closing AGENCY... the closing of the Niagara, North Dakota post office has been filed. It identifies preliminary steps... the Postal Service's determination to close the Niagara post office in Niagara, North Dakota. The...
76 FR 80414 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-12-23
... POSTAL REGULATORY COMMISSION [Docket No. A2012-87; Order No. 1044] Post Office Closing AGENCY... the closing of the Freeport, Kansas post office has been filed. It identifies preliminary steps and... Commission received a petition for review of the Postal Service's determination to close the Freeport post...
76 FR 64978 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-10-19
... POSTAL REGULATORY COMMISSION [Docket No. A2012-8; Order No. 905] Post Office Closing AGENCY... the closing of the Rhodell, West Virginia post office has been filed. It identifies preliminary steps... Postal Service's determination to close the Rhodell post office in Rhodell, West Virginia. The petition...
76 FR 68514 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-11-04
... POSTAL REGULATORY COMMISSION [Docket No. A2012-32; Order No. 938] Post Office Closing AGENCY... the closing of the Barronett, Wisconsin post office has been filed. It identifies preliminary steps... petitions for review of the Postal Service's determination to close the Barronett post office in Barronett...
76 FR 76774 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-12-08
... POSTAL REGULATORY COMMISSION [Docket No. A2012-74; Order No. 1018] Post Office Closing AGENCY... the closing of the Spring Lake, Minnesota post office has been filed. It identifies preliminary steps... Postal Service's determination to close the Spring Lake post office in Spring Lake, Minnesota. The...
76 FR 72728 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-11-25
... POSTAL REGULATORY COMMISSION [Docket No. A2012-52; Order No. 983] Post Office Closing AGENCY... the closing of the Swaledale, Iowa post office has been filed. It identifies preliminary steps and... determination to close the Swaledale post office in Swaledale, Iowa. The first petition for review received...
76 FR 52720 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-08-23
... POSTAL REGULATORY COMMISSION [Docket No. A2011-47; Order No. 805] Post Office Closing AGENCY... the closing of the Francitas, Texas post office has been filed. It identifies preliminary steps and... determination to close the post office in Francitas, Texas. The petition was filed by Carolina Jalufka...
76 FR 45624 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-07-29
... POSTAL REGULATORY COMMISSION [Docket No. A2011-26; Order No. 768] Post Office Closing AGENCY... the closing of the Hamilton, Iowa post office has been filed. It identifies preliminary steps and... to close the post office in Hamilton, Iowa. The petition, which was filed by Bruce Pettyjohn...
76 FR 64979 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-10-19
... POSTAL REGULATORY COMMISSION [Docket No. A2012-9; Order No. 906] Post Office Closing AGENCY... the closing of the Humbird, Wisconsin post office has been filed. It identifies preliminary steps and... Postal Service's determination to close the Humbird post office in Humbird, Wisconsin. The petition for...
77 FR 1958 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2012-01-12
... POSTAL REGULATORY COMMISSION [Docket No. A2012-100; Order No. 1101] Post Office Closing AGENCY... the closing of the Jonesville, Texas post office has been filed. It identifies preliminary steps and... for review of the Postal Service's determination to close the Jonesville post office in Jonesville...
76 FR 46331 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-08-02
... POSTAL REGULATORY COMMISSION [Docket No. A2011-29; Order No. 772] Post Office Closing AGENCY... the closing of the Bigelow, Arkansas post office has been filed. It identifies preliminary steps and... to close the post office in Bigelow, Arkansas. The petition was filed by Brad Akridge, Mayor...
76 FR 69773 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-11-09
... POSTAL REGULATORY COMMISSION [Docket No. A2012-40; Order No. 946] Post Office Closing AGENCY... the closing of the Beech Grove, Kentucky post office has been filed. It identifies preliminary steps... Postal Service's determination to close the Beech Grove post office in Beech Grove, Kentucky. The...
76 FR 46332 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-08-02
... POSTAL REGULATORY COMMISSION [Docket No. A2011-31; Order No. 774] Post Office Closing AGENCY... the closing of the Minneapolis, North Carolina post office has been filed. It identifies preliminary... to close the post office in Minneapolis, North Carolina. The petition was filed by Ryan Carter...
76 FR 68795 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-11-07
... POSTAL REGULATORY COMMISSION [Docket No. A2012-35; Order No. 941] Post Office Closing AGENCY... the closing of the Rembrandt, Iowa post office has been filed. It identifies preliminary steps and... the Postal Service's determination to close the Rembrandt post office in Rembrandt, Iowa. The first...
76 FR 47274 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-08-04
... POSTAL REGULATORY COMMISSION [Docket No. A2011-34; Order No. 782] Post Office Closing AGENCY... the closing of the Innis, Louisiana post office has been filed. It identifies preliminary steps and... to close the post office in Innis, Louisiana. The petition was filed by Larry Rebalais (Petitioner...
Vehicle Support Posts Installation onto Mobile Launcher
2017-05-11
Construction workers on the deck of the mobile launcher prepare the platforms for installation of vehicle support posts at NASA's Kennedy Space Center in Florida. At left, four of the support posts are installed. A total of eight support posts will be installed to support the load of the Space Launch System's (SLS) solid rocket boosters, with four posts for each of the boosters. The support posts are about five feet tall and each weigh about 10,000 pounds. The posts will structurally support the SLS rocket through T-0 and liftoff, and will drop down before vehicle liftoff to avoid contact with the flight hardware. The Ground Systems Development and Operations Program is overseeing installation of the support posts to prepare for the launch of the Orion spacecraft atop the SLS rocket.
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. (a...
76 FR 58544 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-09-21
... POSTAL REGULATORY COMMISSION [Docket No. A2011-71; Order No. 855] Post Office Closing AGENCY... the closing of the Latham, Missouri post office has been filed. It identifies preliminary steps and... determination to close the Latham post office in Latham, Missouri. The petition was filed by Deanna Cook on...
76 FR 62097 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-10-06
... POSTAL REGULATORY COMMISSION [Docket No. A2011-91; Order No. 883] Post Office Closing AGENCY... the closing of the West Stockholm, New York post office has been filed. It identifies preliminary... determination to close the West Stockholm post office in West Stockholm, New York. The petition was filed by...
76 FR 77273 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-12-12
... POSTAL REGULATORY COMMISSION [Docket No. A2012-79; Order No. 1022] Post Office Closing AGENCY... the closing of the Burns, Colorado post office has been filed. It identifies preliminary steps and... determination to close the Burns post office in Burns, Colorado. The first petition for review received November...
77 FR 3807 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2012-01-25
... POSTAL REGULATORY COMMISSION [Docket No. A2012-110; Order No. 1149] Post Office Closing AGENCY... the closing of the Badger, Iowa post office has been filed. It identifies preliminary steps and... for review of the Postal Service's determination to close the Badger post office in Badger, Iowa. The...
76 FR 64127 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-10-17
... POSTAL REGULATORY COMMISSION [Docket No. A2012-1; Order No. 897] Post Office Closing AGENCY... the closing of the Basalt, Idaho post office has been filed. It identifies preliminary steps and... petitions for review of the Postal Service's determination to close the Basalt post office in Basalt, Idaho...
76 FR 71085 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-11-16
... POSTAL REGULATORY COMMISSION [Docket No. A2012-44; Order No. 961] Post Office Closing AGENCY... the closing of the Deer Grove, Illinois post office has been filed. It identifies preliminary steps... for review of the Postal Service's determination to close the Deer Grove post office in Deer Grove...
76 FR 67771 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-11-02
... POSTAL REGULATORY COMMISSION [Docket No. A2012-27; Order No. 932] Post Office Closing AGENCY... the closing of the St. Olaf, Iowa post office has been filed. It identifies preliminary steps and... Postal Service's determination to close the St. Olaf post office in St. Olaf, Iowa. The petition for...
76 FR 67772 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-11-02
... POSTAL REGULATORY COMMISSION [Docket No. A2012-26; Order No. 931] Post Office Closing AGENCY... the closing of the Lodi, Texas post office has been filed. It identifies preliminary steps and... Postal Service's determination to close the Lodi post office in Lodi, Texas. The petition for review was...
76 FR 46857 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-08-03
... POSTAL REGULATORY COMMISSION [Docket No. A2011-33; Order No. 776] Post Office Closing AGENCY... the closing of the Still Pond, Maryland post office has been filed. It identifies preliminary steps... to close the post office in Still Pond, Maryland. The petition was filed by Craig O'Donnell...
76 FR 61403 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-10-04
... POSTAL REGULATORY COMMISSION [Docket No. A2011-86; Order No. 878] Post Office Closing AGENCY... the closing of the Redfield, New York post office has been filed. It identifies preliminary steps and... of the Postal Service's determination to close the Redfield post office in Redfield, New York. The...
76 FR 58546 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-09-21
... POSTAL REGULATORY COMMISSION [Docket No. A2011-72; Order No. 856] Post Office Closing AGENCY... the closing of the Hailesboro, New York post office has been filed. It identifies preliminary steps... determination to close the Hailesboro post office in Hailesboro, New York. The petition was filed by Natalie J...
76 FR 64132 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-10-17
... POSTAL REGULATORY COMMISSION [Docket No. A2012-6; Order No. 902] Post Office Closing AGENCY... the closing of the Saint Lucas, Iowa post office has been filed. It identifies preliminary steps and... Postal Service's determination to close the Saint Lucas post office in Saint Lucas, Iowa. The petition...
76 FR 75568 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-12-02
... POSTAL REGULATORY COMMISSION [Docket No. A2012-59; Order No. 1000] Post Office Closing AGENCY... the closing of the New Cambria, Kansas post office has been filed. It identifies preliminary steps and... Postal Service's determination to close the New Cambria post office in New Cambria, Kansas. The petition...
77 FR 3805 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2012-01-25
... POSTAL REGULATORY COMMISSION [Docket No. A2012-109; Order No. 1148] Post Office Closing AGENCY... the closing of the Bovill, Idaho post office has been filed. It identifies preliminary steps and... petitions for review of the Postal Service's determination to close the Bovill post office in Bovill, Idaho...
77 FR 7213 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2012-02-10
... POSTAL REGULATORY COMMISSION [Docket No. A2012-120; Order No. 1198] Post Office Closing AGENCY... the closing of the Santa Fe, Missouri post office has been filed. It identifies preliminary steps and... two petitions for review of the Postal Service's determination to close the Santa Fe post office in...
76 FR 72985 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-11-28
... POSTAL REGULATORY COMMISSION [Docket No. A2012-53; Order No. 984] Post Office Closing AGENCY... the closing of the Witten, South Dakota post office has been filed. It identifies preliminary steps... determination to close the Witten post office in Witten, South Dakota. The first petition for review received...
76 FR 61758 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-10-05
... POSTAL REGULATORY COMMISSION [Docket No. A2011-89; Order No. 881] Post Office Closing AGENCY... the closing of the Argyle, Florida post office has been filed. It identifies preliminary steps and... determination to close the Argyle post office in Argyle, Florida. The petition was filed by Blythe D. Gottleib...
76 FR 78318 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-12-16
... POSTAL REGULATORY COMMISSION [Docket No. A2012-80; Order No. 1029] Post Office Closing AGENCY... the closing of the Harris, Iowa post office has been filed. It identifies preliminary steps and... received a petition for review of the Postal Service's determination to close the Harris post office in...
76 FR 70173 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-11-10
... POSTAL REGULATORY COMMISSION [Docket No. A2012-41; Order No. 948] Post Office Closing AGENCY... the closing of the West Edmeston, New York post office has been filed. It identifies preliminary steps... Postal Service's determination to close the West Edmeston post office in West Edmeston, New York. The...
77 FR 3808 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2012-01-25
... POSTAL REGULATORY COMMISSION [Docket No. A2012-107; Order No. 1146] Post Office Closing AGENCY... the closing of the Chilo, Ohio post office has been filed. It identifies preliminary steps and... review of the Postal Service's determination to close the Chilo post office in Chilo, Ohio. The petition...
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. (a...
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. (a...
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. (a...
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. (a...
76 FR 62463 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-10-07
... POSTAL REGULATORY COMMISSION [Docket No. A2011-95; Order No. 888] Post Office Closing AGENCY... the closing of the Carolina, West Virginia post office has been filed. It identifies preliminary steps... determination to close the Carolina post office in Carolina, West Virginia. The petition for review was filed by...
75 FR 54402 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2010-09-07
... POSTAL REGULATORY COMMISSION [Docket No. A2010-6; Order No. 527] Post Office Closing AGENCY... the closing of the Renfro Valley Post Office, Renfro Valley, Kentucky 40473, has been filed. It... closing of the Renfro Valley Post Office, Renfro Valley, Kentucky 40473. The appeal, which appears to be...
76 FR 59749 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-09-27
... POSTAL REGULATORY COMMISSION [Docket No. A2011-77; Order No. 866] Post Office Closing AGENCY... the closing of the Martinsburg, New York post office has been filed. It identifies preliminary steps... determination to close the Martinsburg post office in Martinsburg, New York. The petition was filed by the...
77 FR 1962 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2012-01-12
... POSTAL REGULATORY COMMISSION [Docket No. A2012-104; Order No. 1105] Post Office Closing AGENCY... the closing of the Daisy, Georgia post office has been filed. It identifies preliminary steps and... petitions for review of the Postal Service's determination to close the Daisy post office in Daisy, Georgia...
76 FR 60561 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-09-29
... POSTAL REGULATORY COMMISSION [Docket No. A2011-81; Order No. 870] Post Office Closing AGENCY... the closing of the Clarksville, New York post office has been filed. It identifies preliminary steps... determination to close the Clarksville post office in Clarksville, New York. The petition was filed online by...
76 FR 60559 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-09-29
... POSTAL REGULATORY COMMISSION [Docket No. A2011-78; Order No. 867] Post Office Closing AGENCY... the closing of the Smyrna, New York post office has been filed. It identifies preliminary steps and... Postal Service's determination to close the Smyrna post office in Smyrna, New York. The petition was...
76 FR 80413 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-12-23
... POSTAL REGULATORY COMMISSION [Docket No. A2012-88; Order No. 1045] Post Office Closing AGENCY... the closing of the Alplaus, New York post office has been filed. It identifies preliminary steps and... received a petition for review of the Postal Service's determination to close the Alplaus post office in...
76 FR 59453 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-09-26
... POSTAL REGULATORY COMMISSION [Docket No. A2011-76; Order No. 863] Post Office Closing AGENCY... the closing of the Templeville, Maryland post office has been filed. It identifies preliminary steps... determination to close the Ellisburg post office in Ellisburg, New York. The petition was filed by Winford J...
76 FR 58312 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-09-20
... POSTAL REGULATORY COMMISSION [Docket No. A2011-69; Order No. 853] Post Office Closing AGENCY... the closing of the Old Chatham, New York post office has been filed. It identifies preliminary steps... Postal Service's determination to close the Old Chatham post office in Old Chatham, New York. The...
76 FR 63678 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-10-13
... POSTAL REGULATORY COMMISSION [Docket No. A2011-101; Order No. 894] Post Office Closing AGENCY... the closing of the Lorraine, New York post office has been filed. It identifies preliminary steps and... Postal Service's determination to close the Lorraine post office in Lorraine, New York. The petition for...
76 FR 77025 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-12-09
... POSTAL REGULATORY COMMISSION [Docket No. A2012-78; Order No. 1021] Post Office Closing AGENCY... the closing of the Avalon, Texas post office has been filed. It identifies preliminary steps and... for review of the Postal Service's determination to close the Avalon post office in Avalon, Texas. The...
76 FR 57768 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-09-16
... POSTAL REGULATORY COMMISSION [Docket No. A2011-65; Order No. 848] Post Office Closing AGENCY... the closing of the Sharpsburg, Iowa post office has been filed. It identifies preliminary steps and... determination to close the Sharpsburg post office in Sharpsburg, Iowa. The petition was filed by Dean and...
76 FR 62466 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-10-07
... POSTAL REGULATORY COMMISSION [Docket No. A2011-100; Order No. 893] Post Office Closing AGENCY... the closing of the Mallory, New York post office has been filed. It identifies preliminary steps and... Postal Service's determination to close the Mallory post office in Mallory, New York. The petition for...
76 FR 81548 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-12-28
... POSTAL REGULATORY COMMISSION [Docket No. A2012-90; Order No. 1063] Post Office Closing AGENCY... the closing of the Alexander, Kansas post office has been filed. It identifies preliminary steps and... received a petition for review of the Postal Service's determination to close the Alexander post office in...
76 FR 58847 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-09-22
... POSTAL REGULATORY COMMISSION [Docket No. A2011-73; Order No. 858] Post Office Closing AGENCY... the closing of the Langston, Alabama post office has been filed. It identifies preliminary steps and... determination to close the Langston post office in Langston, Alabama. The petition was filed by Donald J. Hahn...
76 FR 46334 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-08-02
... POSTAL REGULATORY COMMISSION [Docket No. A2011-32; Order No. 775] Post Office Closing AGENCY... the closing of the Chillicothe, Iowa post office has been filed. It identifies preliminary steps and... to close the post office in Chillicothe, Iowa. The petition was filed by Jason Van Der Veer...
76 FR 49799 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-08-11
... POSTAL REGULATORY COMMISSION [Docket No. A2011-39; Order No. 793] Post Office Closing AGENCY... the closing of the Ulman, Missouri post office has been filed. It identifies preliminary steps and... determination to close the post office in Ulman, Missouri. The petition was filed by Buster McGowin (Petitioner...
76 FR 48924 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-08-09
... POSTAL REGULATORY COMMISSION [Docket No. A2011-37; Order No. 788] Post Office Closing AGENCY... the closing of the Thayer, Iowa post office has been filed. It identifies preliminary steps and... to close the post office in Thayer, Iowa. The petition was filed by Mike Tonelli (Petitioner) and is...
76 FR 49800 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-08-11
... POSTAL REGULATORY COMMISSION [Docket No. A2011-38; Order No. 792] Post Office Closing AGENCY... the closing of the Masonville, Iowa post office has been filed. It identifies preliminary steps and... determination to close the post office in Masonville, Iowa. The petition was filed by Nellie Marting (Petitioner...
76 FR 69297 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-11-08
... POSTAL REGULATORY COMMISSION [Docket No. A2012-36; Order No. 942] Post Office Closing AGENCY... the closing of the East Poland, Maine post office has been filed. It identifies preliminary steps and... petitions for review of the Postal Service's determination to close the East Poland post office in East...
76 FR 48923 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-08-09
... POSTAL REGULATORY COMMISSION [Docket No. A2011-36; Order No. 787] Post Office Closing AGENCY... the closing of the Hoxie, Iowa post office has been filed. It identifies preliminary steps and... to close the post office in Hoxie, Arkansas. The petition was filed by Lanny Tinker, Mayor of the...
76 FR 59451 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-09-26
... POSTAL REGULATORY COMMISSION [Docket No. A2011-74; Order No. 861] Post Office Closing AGENCY... the closing of the Coyote, New Mexico post office has been filed. It identifies preliminary steps and... determination to close the Coyote post office in Coyote, New Mexico. The petition was filed by Manuelita...
76 FR 61760 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-10-05
... POSTAL REGULATORY COMMISSION [Docket No. A2011-88; Order No. 880 Post Office Closing AGENCY... the closing of the Breaks, Virginia post office has been filed. It identifies preliminary steps and... determination to close the Breaks post office in Breaks, Virginia. The petition was filed by Keith Mullins...
76 FR 62464 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-10-07
... POSTAL REGULATORY COMMISSION [Docket No. A2011-94; Order No. 887] Post Office Closing AGENCY... the closing of the Auburn, West Virginia post office has been filed. It identifies preliminary steps... determination to close the Auburn post office in Auburn, West Virginia. The petition for review was filed by...
76 FR 62468 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-10-07
... POSTAL REGULATORY COMMISSION [Docket No. A2011-99; Order No. 892] Post Office Closing AGENCY... the closing of the Ingleside, Maryland post office has been filed. It identifies preliminary steps and... determination to close the Ingleside post office in Ingleside, Maryland. The petition for review was filed by...
76 FR 62465 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-10-07
... POSTAL REGULATORY COMMISSION [Docket No. A2011-93; Order No. 886] Post Office Closing AGENCY... the closing of the Freedom, Wyoming post office has been filed. It identifies preliminary steps and... determination to close the Freedom post office in Freedom, Wyoming. The first petition for review was filed by...
76 FR 46333 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-08-02
... POSTAL REGULATORY COMMISSION [Docket No. A2011-30; Order No. 773] Post Office Closing AGENCY... the closing of the East Camden Branch, Arkansas post office has been filed. It identifies preliminary... to close the post office in East Camden, Arkansas. The petition was filed by Gene Hill (Petitioner...
76 FR 45301 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-07-28
... POSTAL REGULATORY COMMISSION [Docket No. A2011-25; Order No. 767] Post Office Closing AGENCY... the closing of the Unionville, Iowa post office has been filed. It identifies preliminary steps and... closing of the post office in Unionville, Iowa. The petition, which was filed by Dorothy Jean Smith...
76 FR 49801 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-08-11
... POSTAL REGULATORY COMMISSION [Docket No. A2011-40; Order No. 794] Post Office Closing AGENCY... the closing of the Monroe, Arkansas post office has been filed. It identifies preliminary steps and... determination to close the post office in Monroe, Arkansas. The petition was filed by Martha Pineda (Petitioner...
76 FR 77028 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-12-09
... POSTAL REGULATORY COMMISSION [Docket No. A2012-75; Order No. 1019] Post Office Closing AGENCY... the closing of the Geuda Springs, Kansas post office has been filed. It identifies preliminary steps... determination to close the Geuda Springs post office in Geuda Springs, Kansas. The first petition for review...
76 FR 62462 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-10-07
... POSTAL REGULATORY COMMISSION [Docket No. A2011-96; Order No. 889] Post Office Closing AGENCY... the closing of the West Leyden, New York post office has been filed. It identifies preliminary steps... of the Postal Service's determination to close the West Leyden post office in West Leyden, New York...
76 FR 51435 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-08-18
... POSTAL REGULATORY COMMISSION [Docket No. A2011-44; Order No. 800] Post Office Closing AGENCY... the closing of the Grant, Iowa post office has been filed. It identifies preliminary steps and... determination to close the post office in Grant, Iowa. The petition was filed by Laurenda Mifflin (Petitioner...
76 FR 58314 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-09-20
... POSTAL REGULATORY COMMISSION [Docket No. A2011-68; Order No. 852] Post Office Closing AGENCY... the closing of the Board Camp, Arkansas post office has been filed. It identifies preliminary steps... determination to close the Board Camp post office in Board Camp, Arkansas. The petition was filed by the...
76 FR 60563 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-09-29
... POSTAL REGULATORY COMMISSION [Docket No. A2011-79; Order No. 868] Post Office Closing AGENCY... the closing of the Algoma, Mississippi post office has been filed. It identifies preliminary steps and... determination to close the Algoma post office in Algoma, Mississippi. The petition was filed by Phyllis McGregor...
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…
Vehicle Support Posts Installation at Mobile Launcher
2017-05-11
Construction workers at the Mobile Launcher at NASA's Kennedy Space Center in Florida, prepare to install vehicle support posts. A total of eight support posts are being installed to support the load of the Space Launch System's (SLS) solid rocket boosters, with four posts for each of the boosters. The support posts are about five feet tall and each weigh about 10,000 pounds. The posts will structurally support the SLS rocket through T-0 and liftoff. The Ground Systems Development and Operations Program is overseeing installation of the support posts to prepare for the launch of the Orion spacecraft atop the SLS rocket.
Lucidi, Cynthia de A; de Rezende, Christian L E; Jutkowitz, L Ari; Scott, Michael A
2017-09-01
Precursor-targeted immune-mediated anemia (PIMA) has been suspected in dogs with nonregenerative anemia and bone marrow findings varying from erythroid hyperplasia to pure red cell aplasia. Phagocytosis of erythroid precursors/rubriphagocytosis (RP) reported in some affected dogs suggests a destructive component to the pathogenesis of PIMA. The purpose of the study was to characterize laboratory and clinical findings in dogs with suspected PIMA and RP, with emphasis on cytologic and histologic bone marrow findings. Dogs with PIMA and RP were identified by review of paired bone marrow aspirate and core biopsy slides collected over a 4-year period. Samples were systematically assessed and characterized along with other pertinent laboratory data and clinical findings. Twenty-five dogs met criteria for PIMA and had RP that was relatively stage-selective. Erythropoiesis was expanded to the stage of erythroid precursors undergoing most prominent phagocytosis, yielding patterns characterized by a hypo-, normo-, or hypercellular erythroid lineage. A 4 th pattern involved severe collagen myelofibrosis, and there was a spectrum of mild to severe collagen myelofibrosis overall. Evidence of immune-mediated hemolysis was rare. Immunosuppressive therapy was associated with remission in 77% of dogs treated for at least the median response time of 2 months. Bone marrow patterns in dogs fulfilling criteria for PIMA were aligned with stage-selective phagocytosis of erythroid precursors and the development of collagen myelofibrosis, common in dogs with PIMA. Recognition of these patterns and detection of RP facilitates diagnosis of PIMA, and slow response to immunosuppressive therapy warrants further investigation into its pathogenesis. © 2017 American Society for Veterinary Clinical Pathology.
Post-Traumatic Stress Disorder (PDQ)
... 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 ...
Kathuria, Ambica; Kavitha, M; Khetarpal, Suchit
2011-01-01
Aim: To compare the fracture resistance of teeth restored with fiber-reinforced composite (FRC) posts and experimental dentin posts milled from human root dentin. Materials and Methods: Thirty maxillary central incisors were divided into three groups of ten each. Twenty teeth were restored with FRC posts and solid dentin posts and numbered as Groups 2 and 3 respectively while Group 1 acted as the control, without any post. The teeth were loaded at 135° angle to their long axes after core build-up and the failure loads were recorded. Results: One-way Analysis of Variance (ANOVA) and Bonferroni multiple comparisons revealed a significant difference among test groups with the control group showing the highest fracture resistance, followed by the dentin post group and lastly the FRC post group. Conclusions: Teeth restored with dentin posts exhibited better fracture resistance than those restored with FRC posts. PMID:22144812
76 FR 58545 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-09-21
... POSTAL REGULATORY COMMISSION [Docket No. A2011-70; Order No. 854] Post Office Closing AGENCY... the closing of the Woodgate, New York post office has been filed. It identifies preliminary steps and... determination to close the Woodgate post office in Woodgate, New York. The petition was filed by the Woodgate...
77 FR 4380 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2012-01-27
... POSTAL REGULATORY COMMISSION [Docket No. A2012-114; Order No. 1157] Post Office Closing AGENCY... the closing of the Ponce de Leon, Missouri post office has been filed. It identifies preliminary steps... petition for review of the Postal Service's determination to close the Ponce de Leon Post Office in Ponce...
76 FR 62096 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-10-06
... POSTAL REGULATORY COMMISSION [Docket No. A2011-92; Order No. 884] Post Office Closing AGENCY... determination to close the Redmon post office in Redmon, Illinois. The petition was filed by Jim Cooper, Mayor... determination to close the Redmon post office in Redmon, Illinois. The petition was filed by Jim Cooper, Mayor...
77 FR 1750 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2012-01-11
... POSTAL REGULATORY COMMISSION [Docket No. A2012-99; Order No. 1100] Post Office Closing AGENCY... the closing of the Elk River, Idaho post office has been filed. It identifies preliminary steps and... review of the Postal Service's determination to close the Elk River post office in Elk River, Idaho. The...
76 FR 73744 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-11-29
... POSTAL REGULATORY COMMISSION [Docket No. A2012-57; Order No. 991] Post Office Closing AGENCY... the closing of the Port Kent, New York post office has been filed. It identifies preliminary steps and... Postal Service's determination to close the Port Kent post office in Port Kent, New York. The petition...
76 FR 45625 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-07-29
... POSTAL REGULATORY COMMISSION [Docket No. A2011-27; Order No. 769] Post Office Closing AGENCY... the closing of the Rodney, Iowa post office has been filed. It identifies preliminary steps and... to close the post office in Rodney, Iowa. The petition, which was filed by Zella Thomas, Mayor of the...
76 FR 60945 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-09-30
... POSTAL REGULATORY COMMISSION [Docket No. A2011-82; Order No. 872] Post Office Closing AGENCY... the closing of the Belk, Alabama post office has been filed. It identifies preliminary steps and... determination to close the Belk post office in Belk, Alabama. The petition was filed by Ronald Waldrop, Mayor on...
76 FR 47614 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-08-05
... POSTAL REGULATORY COMMISSION [Docket No. A2011-35; Order No. 786] Post Office Closing AGENCY... the closing of the Pilot Grove, Iowa post office has been filed. It identifies preliminary steps and... determination to close the post office in Pilot Grove, Iowa. The first petition was filed by Sylvan J. Nichting...
76 FR 59452 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-09-26
... POSTAL REGULATORY COMMISSION [Docket No. A2011-75; Order No. 862] Post Office Closing AGENCY... the closing of the Ellisburg, New York post office has been filed. It identifies preliminary steps and... determination to close the Ellisburg post office in Ellisburg, New York. The petition was filed by Winford J...
76 FR 56822 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-09-14
... POSTAL REGULATORY COMMISSION [Docket No. A2011-60; Order No. 841] Post Office Closing AGENCY... the closing of the Gepp, Arkansas post office has been filed. It identifies preliminary steps and... determination to close the Gepp post office in Gepp, Arkansas. The petition was filed online by Kathy Adams on...
76 FR 62460 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-10-07
... POSTAL REGULATORY COMMISSION [Docket No. A2011-98; Order No. 891] Post Office Closing AGENCY... the closing of the La Grande, Washington post office has been filed. It identifies preliminary steps... determination to close the La Grande post office in La Grande, Washington. The petition for review was filed by...
76 FR 60949 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-09-30
... POSTAL REGULATORY COMMISSION [Docket No. A2011-83; Order No. 873] Post Office Closing AGENCY... the closing of the Climax, New York post office has been filed. It identifies preliminary steps and... determination to close the Climax post office in Climax, New York. The petition was filed by Sue Keeler...
76 FR 53159 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-08-25
... POSTAL REGULATORY COMMISSION [Docket No. A2011-48; Order No. 813] Post Office Closing AGENCY... the closing of the Ida, Arkansas post office has been filed. It identifies preliminary steps and... determination to close the post office in Ida, Arkansas. The petition was filed by Earlene Cannon on behalf of...
76 FR 51066 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-08-17
... POSTAL REGULATORY COMMISSION [Docket No. A2011-42; Order No. 798] Post Office Closing AGENCY... the closing of the Rex, North Carolina post office has been filed. It identifies preliminary steps and... determination to close the post office in Rex, North Carolina. The petition was filed by James E. Shaw...
76 FR 51067 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-08-17
... POSTAL REGULATORY COMMISSION [Docket No. A2011-43; Order No. 799] Post Office Closing AGENCY... the closing of the Stoy, Illinois post office has been filed. It identifies preliminary steps and... determination to close the post office in Stoy, Illinois. The petition was filed by Lisa L. McKinley (Petitioner...
45 CFR 160.544 - Post hearing briefs.
Code of Federal Regulations, 2011 CFR
2011-10-01
... REQUIREMENTS GENERAL ADMINISTRATIVE REQUIREMENTS Procedures for Hearings § 160.544 Post hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing... 45 Public Welfare 1 2011-10-01 2011-10-01 false Post hearing briefs. 160.544 Section 160.544...
45 CFR 160.544 - Post hearing briefs.
Code of Federal Regulations, 2014 CFR
2014-10-01
... REQUIREMENTS GENERAL ADMINISTRATIVE REQUIREMENTS Procedures for Hearings § 160.544 Post hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing... 45 Public Welfare 1 2014-10-01 2014-10-01 false Post hearing briefs. 160.544 Section 160.544...
45 CFR 160.544 - Post hearing briefs.
Code of Federal Regulations, 2012 CFR
2012-10-01
... REQUIREMENTS GENERAL ADMINISTRATIVE REQUIREMENTS Procedures for Hearings § 160.544 Post hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing... 45 Public Welfare 1 2012-10-01 2012-10-01 false Post hearing briefs. 160.544 Section 160.544...
45 CFR 160.544 - Post hearing briefs.
Code of Federal Regulations, 2013 CFR
2013-10-01
... REQUIREMENTS GENERAL ADMINISTRATIVE REQUIREMENTS Procedures for Hearings § 160.544 Post hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing... 45 Public Welfare 1 2013-10-01 2013-10-01 false Post hearing briefs. 160.544 Section 160.544...
45 CFR 160.544 - Post hearing briefs.
Code of Federal Regulations, 2010 CFR
2010-10-01
... REQUIREMENTS GENERAL ADMINISTRATIVE REQUIREMENTS Procedures for Hearings § 160.544 Post hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing... 45 Public Welfare 1 2010-10-01 2010-10-01 false Post hearing briefs. 160.544 Section 160.544...
MARS Science Laboratory Post-Landing Location Estimation Using Post2 Trajectory Simulation
NASA Technical Reports Server (NTRS)
Davis, J. L.; Shidner, Jeremy D.; Way, David W.
2013-01-01
The Mars Science Laboratory (MSL) Curiosity rover landed safely on Mars August 5th, 2012 at 10:32 PDT, Earth Received Time. Immediately following touchdown confirmation, best estimates of position were calculated to assist in determining official MSL locations during entry, descent and landing (EDL). Additionally, estimated balance mass impact locations were provided and used to assess how predicted locations compared to actual locations. For MSL, the Program to Optimize Simulated Trajectories II (POST2) was the primary trajectory simulation tool used to predict and assess EDL performance from cruise stage separation through rover touchdown and descent stage impact. This POST2 simulation was used during MSL operations for EDL trajectory analyses in support of maneuver decisions and imaging MSL during EDL. This paper presents the simulation methodology used and results of pre/post-landing MSL location estimates and associated imagery from Mars Reconnaissance Orbiter s (MRO) High Resolution Imaging Science Experiment (HiRISE) camera. To generate these estimates, the MSL POST2 simulation nominal and Monte Carlo data, flight telemetry from onboard navigation, relay orbiter positions from MRO and Mars Odyssey and HiRISE generated digital elevation models (DEM) were utilized. A comparison of predicted rover and balance mass location estimations against actual locations are also presented.
Mechanical properties and micro-morphology of fiber posts.
Zicari, F; Coutinho, E; Scotti, R; Van Meerbeek, B; Naert, I
2013-04-01
To evaluate flexural properties of different fiber posts systems and to morphologically characterize their micro-structure. Six types of translucent fiber posts were selected: RelyX Post (3M ESPE), ParaPost Taper Lux (Colthéne-Whaledent), GC Fiber Post (GC), LuxaPost (DMG), FRC Postec Plus (Ivoclar-Vivadent), D.T. Light-Post (RTD). For each post system and size, ten specimens were subjected to a three-points bending test. Maximum fracture load, flexural strength and flexural modulus were determined using a universal loading device (5848 MicroTester(®), Instron). Besides, for each system, three intact posts of similar dimensions were processed for scanning electron microscopy to morphologically characterize the micro-structure. The following structural characteristics were analyzed: fibers/matrix ratio, density of fibers, diameter of fibers and distribution of fibers. Data were statistically analyzed with ANOVA. Type and diameter of posts were found to significantly affect the fracture load, flexural strength and flexural modulus (p<0.05). Regarding maximum fracture load, it was found to increase with post diameter, in each post system (p<0.001). Regarding flexural strength and flexural modulus, the highest values were recorded for posts with the smallest diameter (p<0.001). Finally, structural characteristics significantly varied among the post systems tested. However, any correlation has been found between flexural strength and structural characteristics. Flexural strength appeared not to be correlated to structural characteristics of fiber posts, but it may rather be affected by mechanical properties of the resin matrix and the interfacial adhesion between fibers and resin matrix. Copyright © 2013. Published by Elsevier Ltd.
Post Traumatic Stress Disorder: The Facts
2007-02-22
Post Traumatic Stress Disorder ( PTSD ... PTSD treated? POST TRAUMATIC STRESS DISORDER : THE FACTS! He who did well in war, earns the right to begin doing well in peace. —Robert...Department of Veterans Affairs (VA), the National Center for Post Traumatic Stress Disorder (NC- PTSD ), the Walter Reed Army Medical Center (WRAMC),
75 FR 4429 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2010-01-27
... POSTAL REGULATORY COMMISSION [Docket No. A2010-2; Order No. 395] Post Office Closing AGENCY... the closing of the Sundance, CO, post office has been filed. It identifies preliminary steps and... to 39 U.S.C. 404(d), the Commission has received an appeal of the closing of the Sundance post office...
76 FR 62461 - Post Office Closing
Federal Register 2010, 2011, 2012, 2013, 2014
2011-10-07
... POSTAL REGULATORY COMMISSION [Docket No. A2011-97; Order No. 890] Post Office Closing AGENCY... the closing of the Oak Hill, Alabama post office has been filed. It identifies preliminary steps and... determination to close the Oak Hill post office in Oak Hill, Alabama. The petition for review was filed by the...
Post-Flight Data Analysis Tool
NASA Technical Reports Server (NTRS)
George, Marina
2018-01-01
A software tool that facilitates the retrieval and analysis of post-flight data. This allows our team and other teams to effectively and efficiently analyze and evaluate post-flight data in order to certify commercial providers.
38 CFR 42.36 - Post-hearing briefs.
Code of Federal Regulations, 2011 CFR
2011-07-01
...) STANDARDS IMPLEMENTING THE PROGRAM FRAUD CIVIL REMEDIES ACT § 42.36 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief. The... 38 Pensions, Bonuses, and Veterans' Relief 2 2011-07-01 2011-07-01 false Post-hearing briefs. 42...
49 CFR 31.36 - Post-hearing briefs.
Code of Federal Regulations, 2014 CFR
2014-10-01
... 49 Transportation 1 2014-10-01 2014-10-01 false Post-hearing briefs. 31.36 Section 31.36 Transportation Office of the Secretary of Transportation PROGRAM FRAUD CIVIL REMEDIES § 31.36 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post...
38 CFR 42.36 - Post-hearing briefs.
Code of Federal Regulations, 2014 CFR
2014-07-01
...) STANDARDS IMPLEMENTING THE PROGRAM FRAUD CIVIL REMEDIES ACT § 42.36 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief. The... 38 Pensions, Bonuses, and Veterans' Relief 2 2014-07-01 2014-07-01 false Post-hearing briefs. 42...
38 CFR 42.36 - Post-hearing briefs.
Code of Federal Regulations, 2012 CFR
2012-07-01
...) STANDARDS IMPLEMENTING THE PROGRAM FRAUD CIVIL REMEDIES ACT § 42.36 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief. The... 38 Pensions, Bonuses, and Veterans' Relief 2 2012-07-01 2012-07-01 false Post-hearing briefs. 42...
49 CFR 31.36 - Post-hearing briefs.
Code of Federal Regulations, 2011 CFR
2011-10-01
... 49 Transportation 1 2011-10-01 2011-10-01 false Post-hearing briefs. 31.36 Section 31.36 Transportation Office of the Secretary of Transportation PROGRAM FRAUD CIVIL REMEDIES § 31.36 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post...
49 CFR 31.36 - Post-hearing briefs.
Code of Federal Regulations, 2010 CFR
2010-10-01
... 49 Transportation 1 2010-10-01 2010-10-01 false Post-hearing briefs. 31.36 Section 31.36 Transportation Office of the Secretary of Transportation PROGRAM FRAUD CIVIL REMEDIES § 31.36 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post...
38 CFR 42.36 - Post-hearing briefs.
Code of Federal Regulations, 2013 CFR
2013-07-01
...) STANDARDS IMPLEMENTING THE PROGRAM FRAUD CIVIL REMEDIES ACT § 42.36 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief. The... 38 Pensions, Bonuses, and Veterans' Relief 2 2013-07-01 2013-07-01 false Post-hearing briefs. 42...
49 CFR 31.36 - Post-hearing briefs.
Code of Federal Regulations, 2012 CFR
2012-10-01
... 49 Transportation 1 2012-10-01 2012-10-01 false Post-hearing briefs. 31.36 Section 31.36 Transportation Office of the Secretary of Transportation PROGRAM FRAUD CIVIL REMEDIES § 31.36 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post...
38 CFR 42.36 - Post-hearing briefs.
Code of Federal Regulations, 2010 CFR
2010-07-01
...) STANDARDS IMPLEMENTING THE PROGRAM FRAUD CIVIL REMEDIES ACT § 42.36 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief. The... 38 Pensions, Bonuses, and Veterans' Relief 2 2010-07-01 2010-07-01 false Post-hearing briefs. 42...
49 CFR 31.36 - Post-hearing briefs.
Code of Federal Regulations, 2013 CFR
2013-10-01
... 49 Transportation 1 2013-10-01 2013-10-01 false Post-hearing briefs. 31.36 Section 31.36 Transportation Office of the Secretary of Transportation PROGRAM FRAUD CIVIL REMEDIES § 31.36 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post...
Post-Deployment Memorial Ceremony: A Vital Link
2008-03-25
stress and possible post traumatic stress disorder ( PTSD ). Post - deployment memorial ceremonies provide the final link to...grieved in the allotted time provided at a memorial ceremony. Research into post - traumatic stress disorder ( PTSD ) indicates the cumulative effects...New York: Atheneum, 1994), 40. 38 Glenn R. Schiraldi, The Post – Traumatic Stress Disorder Sourcebook (Los Angeles: Lowell House, 2000),
12 CFR 308.535 - Post-hearing briefs.
Code of Federal Regulations, 2011 CFR
2011-01-01
... PRACTICE AND PROCEDURE Program Fraud Civil Remedies and Procedures § 308.535 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing... 12 Banks and Banking 4 2011-01-01 2011-01-01 false Post-hearing briefs. 308.535 Section 308.535...
42 CFR 3.544 - Post hearing briefs.
Code of Federal Regulations, 2010 CFR
2010-10-01
... ORGANIZATIONS AND PATIENT SAFETY WORK PRODUCT Enforcement Program § 3.544 Post hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief... 42 Public Health 1 2010-10-01 2010-10-01 false Post hearing briefs. 3.544 Section 3.544 Public...
42 CFR 3.544 - Post hearing briefs.
Code of Federal Regulations, 2014 CFR
2014-10-01
... ORGANIZATIONS AND PATIENT SAFETY WORK PRODUCT Enforcement Program § 3.544 Post hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief... 42 Public Health 1 2014-10-01 2014-10-01 false Post hearing briefs. 3.544 Section 3.544 Public...
20 CFR 355.36 - Post-hearing briefs.
Code of Federal Regulations, 2014 CFR
2014-04-01
... REGULATIONS UNDER THE PROGRAM FRAUD CIVIL REMEDIES ACT OF 1986 § 355.36 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief... 20 Employees' Benefits 1 2014-04-01 2012-04-01 true Post-hearing briefs. 355.36 Section 355.36...
47 CFR 25.165 - Posting of bonds.
Code of Federal Regulations, 2014 CFR
2014-10-01
... to post a bond within 30 days of the grant of its license. Failure to post a bond will render the license null and void automatically. (1) NGSO licensees are required to post a bond in the amount of $5 million. (2) GSO licensees are required to post a bond in the amount of $3 million. (3) Licensees of...
28 CFR 71.36 - Post-hearing briefs.
Code of Federal Regulations, 2014 CFR
2014-07-01
....36 Post-hearing briefs. ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief. The ALJ shall fix the time for filing such briefs, not to exceed 60... 28 Judicial Administration 2 2014-07-01 2014-07-01 false Post-hearing briefs. 71.36 Section 71.36...
47 CFR 25.165 - Posting of bonds.
Code of Federal Regulations, 2010 CFR
2010-10-01
... to post a bond within 30 days of the grant of its license. Failure to post a bond will render the license null and void automatically. (1) NGSO licensees are required to post a bond in the amount of $5 million. (2) GSO licensees are required to post a bond in the amount of $3 million. (3) Licensees of...
15 CFR 25.36 - Post-hearing briefs.
Code of Federal Regulations, 2013 CFR
2013-01-01
....36 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief. The ALJ shall fix the time for filing such briefs, not to... 15 Commerce and Foreign Trade 1 2013-01-01 2013-01-01 false Post-hearing briefs. 25.36 Section 25...
15 CFR 25.36 - Post-hearing briefs.
Code of Federal Regulations, 2010 CFR
2010-01-01
....36 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief. The ALJ shall fix the time for filing such briefs, not to... 15 Commerce and Foreign Trade 1 2010-01-01 2010-01-01 false Post-hearing briefs. 25.36 Section 25...
7 CFR 1.334 - Post-hearing briefs.
Code of Federal Regulations, 2013 CFR
2013-01-01
... Hearings Under the Program Fraud Civil Remedies Act of 1986 § 1.334 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief... 7 Agriculture 1 2013-01-01 2013-01-01 false Post-hearing briefs. 1.334 Section 1.334 Agriculture...
40 CFR 27.36 - Post-hearing briefs.
Code of Federal Regulations, 2010 CFR
2010-07-01
... § 27.36 Post-hearing briefs. The presiding officer may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief. The presiding officer shall fix the time for... 40 Protection of Environment 1 2010-07-01 2010-07-01 false Post-hearing briefs. 27.36 Section 27...
6 CFR 13.36 - Post-hearing briefs.
Code of Federal Regulations, 2011 CFR
2011-01-01
... § 13.36 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief. The ALJ will fix the time for filing such briefs. Such briefs... 6 Domestic Security 1 2011-01-01 2011-01-01 false Post-hearing briefs. 13.36 Section 13.36...
20 CFR 355.36 - Post-hearing briefs.
Code of Federal Regulations, 2010 CFR
2010-04-01
... REGULATIONS UNDER THE PROGRAM FRAUD CIVIL REMEDIES ACT OF 1986 § 355.36 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief... 20 Employees' Benefits 1 2010-04-01 2010-04-01 false Post-hearing briefs. 355.36 Section 355.36...
12 CFR 308.535 - Post-hearing briefs.
Code of Federal Regulations, 2012 CFR
2012-01-01
... PRACTICE AND PROCEDURE Program Fraud Civil Remedies and Procedures § 308.535 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing... 12 Banks and Banking 5 2012-01-01 2012-01-01 false Post-hearing briefs. 308.535 Section 308.535...
7 CFR 1.334 - Post-hearing briefs.
Code of Federal Regulations, 2010 CFR
2010-01-01
... Hearings Under the Program Fraud Civil Remedies Act of 1986 § 1.334 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief... 7 Agriculture 1 2010-01-01 2010-01-01 false Post-hearing briefs. 1.334 Section 1.334 Agriculture...
29 CFR 22.36 - Post-hearing briefs.
Code of Federal Regulations, 2011 CFR
2011-07-01
... 29 Labor 1 2011-07-01 2011-07-01 false Post-hearing briefs. 22.36 Section 22.36 Labor Office of the Secretary of Labor PROGRAM FRAUD CIVIL REMEDIES ACT OF 1986 § 22.36 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing...
6 CFR 13.36 - Post-hearing briefs.
Code of Federal Regulations, 2013 CFR
2013-01-01
... § 13.36 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief. The ALJ will fix the time for filing such briefs. Such briefs... 6 Domestic Security 1 2013-01-01 2013-01-01 false Post-hearing briefs. 13.36 Section 13.36...
12 CFR 308.535 - Post-hearing briefs.
Code of Federal Regulations, 2014 CFR
2014-01-01
... PRACTICE AND PROCEDURE Program Fraud Civil Remedies and Procedures § 308.535 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing... 12 Banks and Banking 5 2014-01-01 2014-01-01 false Post-hearing briefs. 308.535 Section 308.535...
40 CFR 27.36 - Post-hearing briefs.
Code of Federal Regulations, 2014 CFR
2014-07-01
... § 27.36 Post-hearing briefs. The presiding officer may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief. The presiding officer shall fix the time for... 40 Protection of Environment 1 2014-07-01 2014-07-01 false Post-hearing briefs. 27.36 Section 27...
10 CFR 13.36 - Post-hearing briefs.
Code of Federal Regulations, 2013 CFR
2013-01-01
... 10 Energy 1 2013-01-01 2013-01-01 false Post-hearing briefs. 13.36 Section 13.36 Energy NUCLEAR REGULATORY COMMISSION PROGRAM FRAUD CIVIL REMEDIES § 13.36 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief. The ALJ shall...
10 CFR 13.36 - Post-hearing briefs.
Code of Federal Regulations, 2011 CFR
2011-01-01
... 10 Energy 1 2011-01-01 2011-01-01 false Post-hearing briefs. 13.36 Section 13.36 Energy NUCLEAR REGULATORY COMMISSION PROGRAM FRAUD CIVIL REMEDIES § 13.36 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief. The ALJ shall...
28 CFR 71.36 - Post-hearing briefs.
Code of Federal Regulations, 2013 CFR
2013-07-01
....36 Post-hearing briefs. ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief. The ALJ shall fix the time for filing such briefs, not to exceed 60... 28 Judicial Administration 2 2013-07-01 2013-07-01 false Post-hearing briefs. 71.36 Section 71.36...
5 CFR 185.136 - Post-hearing briefs.
Code of Federal Regulations, 2013 CFR
2013-01-01
... CIVIL REMEDIES § 185.136 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief. The ALJ shall fix the time for filing such... 5 Administrative Personnel 1 2013-01-01 2013-01-01 false Post-hearing briefs. 185.136 Section 185...
7 CFR 1.334 - Post-hearing briefs.
Code of Federal Regulations, 2014 CFR
2014-01-01
... Hearings Under the Program Fraud Civil Remedies Act of 1986 § 1.334 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief... 7 Agriculture 1 2014-01-01 2014-01-01 false Post-hearing briefs. 1.334 Section 1.334 Agriculture...
28 CFR 71.36 - Post-hearing briefs.
Code of Federal Regulations, 2010 CFR
2010-07-01
....36 Post-hearing briefs. ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief. The ALJ shall fix the time for filing such briefs, not to exceed 60... 28 Judicial Administration 2 2010-07-01 2010-07-01 false Post-hearing briefs. 71.36 Section 71.36...
42 CFR 1005.19 - Post-hearing briefs.
Code of Federal Regulations, 2014 CFR
2014-10-01
... APPEALS OF EXCLUSIONS, CIVIL MONEY PENALTIES AND ASSESSMENTS § 1005.19 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief... 42 Public Health 5 2014-10-01 2014-10-01 false Post-hearing briefs. 1005.19 Section 1005.19 Public...
42 CFR 1005.19 - Post-hearing briefs.
Code of Federal Regulations, 2011 CFR
2011-10-01
... APPEALS OF EXCLUSIONS, CIVIL MONEY PENALTIES AND ASSESSMENTS § 1005.19 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief... 42 Public Health 5 2011-10-01 2011-10-01 false Post-hearing briefs. 1005.19 Section 1005.19 Public...
28 CFR 71.36 - Post-hearing briefs.
Code of Federal Regulations, 2012 CFR
2012-07-01
....36 Post-hearing briefs. ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief. The ALJ shall fix the time for filing such briefs, not to exceed 60... 28 Judicial Administration 2 2012-07-01 2012-07-01 false Post-hearing briefs. 71.36 Section 71.36...
40 CFR 27.36 - Post-hearing briefs.
Code of Federal Regulations, 2011 CFR
2011-07-01
... § 27.36 Post-hearing briefs. The presiding officer may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief. The presiding officer shall fix the time for... 40 Protection of Environment 1 2011-07-01 2011-07-01 false Post-hearing briefs. 27.36 Section 27...
5 CFR 185.136 - Post-hearing briefs.
Code of Federal Regulations, 2012 CFR
2012-01-01
... CIVIL REMEDIES § 185.136 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief. The ALJ shall fix the time for filing such... 5 Administrative Personnel 1 2012-01-01 2012-01-01 false Post-hearing briefs. 185.136 Section 185...
12 CFR 308.535 - Post-hearing briefs.
Code of Federal Regulations, 2010 CFR
2010-01-01
... PRACTICE AND PROCEDURE Program Fraud Civil Remedies and Procedures § 308.535 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing... 12 Banks and Banking 4 2010-01-01 2010-01-01 false Post-hearing briefs. 308.535 Section 308.535...
28 CFR 71.36 - Post-hearing briefs.
Code of Federal Regulations, 2011 CFR
2011-07-01
....36 Post-hearing briefs. ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief. The ALJ shall fix the time for filing such briefs, not to exceed 60... 28 Judicial Administration 2 2011-07-01 2011-07-01 false Post-hearing briefs. 71.36 Section 71.36...
45 CFR 79.36 - Post-hearing briefs.
Code of Federal Regulations, 2012 CFR
2012-10-01
....36 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief. The ALJ shall fix the time for filing such briefs, not to... 45 Public Welfare 1 2012-10-01 2012-10-01 false Post-hearing briefs. 79.36 Section 79.36 Public...
42 CFR 3.544 - Post hearing briefs.
Code of Federal Regulations, 2012 CFR
2012-10-01
... ORGANIZATIONS AND PATIENT SAFETY WORK PRODUCT Enforcement Program § 3.544 Post hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief... 42 Public Health 1 2012-10-01 2012-10-01 false Post hearing briefs. 3.544 Section 3.544 Public...
15 CFR 25.36 - Post-hearing briefs.
Code of Federal Regulations, 2012 CFR
2012-01-01
....36 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief. The ALJ shall fix the time for filing such briefs, not to... 15 Commerce and Foreign Trade 1 2012-01-01 2012-01-01 false Post-hearing briefs. 25.36 Section 25...
40 CFR 27.36 - Post-hearing briefs.
Code of Federal Regulations, 2012 CFR
2012-07-01
... § 27.36 Post-hearing briefs. The presiding officer may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief. The presiding officer shall fix the time for... 40 Protection of Environment 1 2012-07-01 2012-07-01 false Post-hearing briefs. 27.36 Section 27...
5 CFR 185.136 - Post-hearing briefs.
Code of Federal Regulations, 2011 CFR
2011-01-01
... CIVIL REMEDIES § 185.136 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief. The ALJ shall fix the time for filing such... 5 Administrative Personnel 1 2011-01-01 2011-01-01 false Post-hearing briefs. 185.136 Section 185...
42 CFR 3.544 - Post hearing briefs.
Code of Federal Regulations, 2011 CFR
2011-10-01
... ORGANIZATIONS AND PATIENT SAFETY WORK PRODUCT Enforcement Program § 3.544 Post hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief... 42 Public Health 1 2011-10-01 2011-10-01 false Post hearing briefs. 3.544 Section 3.544 Public...
6 CFR 13.36 - Post-hearing briefs.
Code of Federal Regulations, 2012 CFR
2012-01-01
... § 13.36 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief. The ALJ will fix the time for filing such briefs. Such briefs... 6 Domestic Security 1 2012-01-01 2012-01-01 false Post-hearing briefs. 13.36 Section 13.36...
7 CFR 1.334 - Post-hearing briefs.
Code of Federal Regulations, 2012 CFR
2012-01-01
... Hearings Under the Program Fraud Civil Remedies Act of 1986 § 1.334 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief... 7 Agriculture 1 2012-01-01 2012-01-01 false Post-hearing briefs. 1.334 Section 1.334 Agriculture...
10 CFR 13.36 - Post-hearing briefs.
Code of Federal Regulations, 2014 CFR
2014-01-01
... 10 Energy 1 2014-01-01 2014-01-01 false Post-hearing briefs. 13.36 Section 13.36 Energy NUCLEAR REGULATORY COMMISSION PROGRAM FRAUD CIVIL REMEDIES § 13.36 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief. The ALJ shall...
42 CFR 1005.19 - Post-hearing briefs.
Code of Federal Regulations, 2010 CFR
2010-10-01
... APPEALS OF EXCLUSIONS, CIVIL MONEY PENALTIES AND ASSESSMENTS § 1005.19 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief... 42 Public Health 5 2010-10-01 2010-10-01 false Post-hearing briefs. 1005.19 Section 1005.19 Public...
47 CFR 25.165 - Posting of bonds.
Code of Federal Regulations, 2011 CFR
2011-10-01
... to post a bond within 30 days of the grant of its license. Failure to post a bond will render the license null and void automatically. (1) NGSO licensees are required to post a bond in the amount of $5 million. (2) GSO licensees are required to post a bond in the amount of $3 million. (3) Licensees of...
47 CFR 25.165 - Posting of bonds.
Code of Federal Regulations, 2012 CFR
2012-10-01
... to post a bond within 30 days of the grant of its license. Failure to post a bond will render the license null and void automatically. (1) NGSO licensees are required to post a bond in the amount of $5 million. (2) GSO licensees are required to post a bond in the amount of $3 million. (3) Licensees of...
42 CFR 1005.19 - Post-hearing briefs.
Code of Federal Regulations, 2013 CFR
2013-10-01
... APPEALS OF EXCLUSIONS, CIVIL MONEY PENALTIES AND ASSESSMENTS § 1005.19 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief... 42 Public Health 5 2013-10-01 2013-10-01 false Post-hearing briefs. 1005.19 Section 1005.19 Public...
40 CFR 27.36 - Post-hearing briefs.
Code of Federal Regulations, 2013 CFR
2013-07-01
... § 27.36 Post-hearing briefs. The presiding officer may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief. The presiding officer shall fix the time for... 40 Protection of Environment 1 2013-07-01 2013-07-01 false Post-hearing briefs. 27.36 Section 27...
20 CFR 355.36 - Post-hearing briefs.
Code of Federal Regulations, 2011 CFR
2011-04-01
... REGULATIONS UNDER THE PROGRAM FRAUD CIVIL REMEDIES ACT OF 1986 § 355.36 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief... 20 Employees' Benefits 1 2011-04-01 2011-04-01 false Post-hearing briefs. 355.36 Section 355.36...
12 CFR 308.535 - Post-hearing briefs.
Code of Federal Regulations, 2013 CFR
2013-01-01
... PRACTICE AND PROCEDURE Program Fraud Civil Remedies and Procedures § 308.535 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing... 12 Banks and Banking 5 2013-01-01 2013-01-01 false Post-hearing briefs. 308.535 Section 308.535...
5 CFR 185.136 - Post-hearing briefs.
Code of Federal Regulations, 2010 CFR
2010-01-01
... CIVIL REMEDIES § 185.136 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief. The ALJ shall fix the time for filing such... 5 Administrative Personnel 1 2010-01-01 2010-01-01 false Post-hearing briefs. 185.136 Section 185...
10 CFR 13.36 - Post-hearing briefs.
Code of Federal Regulations, 2010 CFR
2010-01-01
... 10 Energy 1 2010-01-01 2010-01-01 false Post-hearing briefs. 13.36 Section 13.36 Energy NUCLEAR REGULATORY COMMISSION PROGRAM FRAUD CIVIL REMEDIES § 13.36 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief. The ALJ shall...
45 CFR 79.36 - Post-hearing briefs.
Code of Federal Regulations, 2014 CFR
2014-10-01
....36 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief. The ALJ shall fix the time for filing such briefs, not to... 45 Public Welfare 1 2014-10-01 2014-10-01 false Post-hearing briefs. 79.36 Section 79.36 Public...
20 CFR 355.36 - Post-hearing briefs.
Code of Federal Regulations, 2013 CFR
2013-04-01
... REGULATIONS UNDER THE PROGRAM FRAUD CIVIL REMEDIES ACT OF 1986 § 355.36 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief... 20 Employees' Benefits 1 2013-04-01 2012-04-01 true Post-hearing briefs. 355.36 Section 355.36...
45 CFR 79.36 - Post-hearing briefs.
Code of Federal Regulations, 2011 CFR
2011-10-01
....36 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief. The ALJ shall fix the time for filing such briefs, not to... 45 Public Welfare 1 2011-10-01 2011-10-01 false Post-hearing briefs. 79.36 Section 79.36 Public...
29 CFR 22.36 - Post-hearing briefs.
Code of Federal Regulations, 2013 CFR
2013-07-01
... 29 Labor 1 2013-07-01 2013-07-01 false Post-hearing briefs. 22.36 Section 22.36 Labor Office of the Secretary of Labor PROGRAM FRAUD CIVIL REMEDIES ACT OF 1986 § 22.36 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing...
5 CFR 185.136 - Post-hearing briefs.
Code of Federal Regulations, 2014 CFR
2014-01-01
... CIVIL REMEDIES § 185.136 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief. The ALJ shall fix the time for filing such... 5 Administrative Personnel 1 2014-01-01 2014-01-01 false Post-hearing briefs. 185.136 Section 185...
47 CFR 25.165 - Posting of bonds.
Code of Federal Regulations, 2013 CFR
2013-10-01
... to post a bond within 30 days of the grant of its license. Failure to post a bond will render the license null and void automatically. (1) NGSO licensees are required to post a bond in the amount of $5 million. (2) GSO licensees are required to post a bond in the amount of $3 million. (3) Licensees of...
6 CFR 13.36 - Post-hearing briefs.
Code of Federal Regulations, 2014 CFR
2014-01-01
... § 13.36 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief. The ALJ will fix the time for filing such briefs. Such briefs... 6 Domestic Security 1 2014-01-01 2014-01-01 false Post-hearing briefs. 13.36 Section 13.36...
7 CFR 1.334 - Post-hearing briefs.
Code of Federal Regulations, 2011 CFR
2011-01-01
... Hearings Under the Program Fraud Civil Remedies Act of 1986 § 1.334 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief... 7 Agriculture 1 2011-01-01 2011-01-01 false Post-hearing briefs. 1.334 Section 1.334 Agriculture...
42 CFR 3.544 - Post hearing briefs.
Code of Federal Regulations, 2013 CFR
2013-10-01
... ORGANIZATIONS AND PATIENT SAFETY WORK PRODUCT Enforcement Program § 3.544 Post hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief... 42 Public Health 1 2013-10-01 2013-10-01 false Post hearing briefs. 3.544 Section 3.544 Public...
15 CFR 25.36 - Post-hearing briefs.
Code of Federal Regulations, 2014 CFR
2014-01-01
....36 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief. The ALJ shall fix the time for filing such briefs, not to... 15 Commerce and Foreign Trade 1 2014-01-01 2014-01-01 false Post-hearing briefs. 25.36 Section 25...
29 CFR 22.36 - Post-hearing briefs.
Code of Federal Regulations, 2012 CFR
2012-07-01
... 29 Labor 1 2012-07-01 2012-07-01 false Post-hearing briefs. 22.36 Section 22.36 Labor Office of the Secretary of Labor PROGRAM FRAUD CIVIL REMEDIES ACT OF 1986 § 22.36 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing...
10 CFR 13.36 - Post-hearing briefs.
Code of Federal Regulations, 2012 CFR
2012-01-01
... 10 Energy 1 2012-01-01 2012-01-01 false Post-hearing briefs. 13.36 Section 13.36 Energy NUCLEAR REGULATORY COMMISSION PROGRAM FRAUD CIVIL REMEDIES § 13.36 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief. The ALJ shall...
15 CFR 25.36 - Post-hearing briefs.
Code of Federal Regulations, 2011 CFR
2011-01-01
....36 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief. The ALJ shall fix the time for filing such briefs, not to... 15 Commerce and Foreign Trade 1 2011-01-01 2011-01-01 false Post-hearing briefs. 25.36 Section 25...
42 CFR 1005.19 - Post-hearing briefs.
Code of Federal Regulations, 2012 CFR
2012-10-01
... APPEALS OF EXCLUSIONS, CIVIL MONEY PENALTIES AND ASSESSMENTS § 1005.19 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief... 42 Public Health 5 2012-10-01 2012-10-01 false Post-hearing briefs. 1005.19 Section 1005.19 Public...
20 CFR 355.36 - Post-hearing briefs.
Code of Federal Regulations, 2012 CFR
2012-04-01
... REGULATIONS UNDER THE PROGRAM FRAUD CIVIL REMEDIES ACT OF 1986 § 355.36 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief... 20 Employees' Benefits 1 2012-04-01 2012-04-01 false Post-hearing briefs. 355.36 Section 355.36...
45 CFR 79.36 - Post-hearing briefs.
Code of Federal Regulations, 2013 CFR
2013-10-01
....36 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief. The ALJ shall fix the time for filing such briefs, not to... 45 Public Welfare 1 2013-10-01 2013-10-01 false Post-hearing briefs. 79.36 Section 79.36 Public...
[Research progress in post-fire debris flow].
Di, Xue-ying; Tao, Yu-zhu
2013-08-01
The occurrence of the secondary disasters of forest fire has significant impacts on the environment quality and human health and safety. Post-fire debris flow is one of the most hazardous secondary disasters of forest fire. To understand the occurrence conditions of post-fire debris flow and to master its occurrence situation are the critical elements in post-fire hazard assessment. From the viewpoints of vegetation, precipitation threshold and debris flow material sources, this paper elaborated the impacts of forest fire on the debris flow, analyzed the geologic and geomorphic conditions, precipitation and slope condition that caused the post-fire debris flow as well as the primary mechanisms of debris-flow initiation caused by shallow landslide or surface runoff, and reviewed the research progress in the prediction and forecast of post-fire debris flow and the related control measures. In the future research, four aspects to be focused on were proposed, i. e., the quantification of the relationships between the fire behaviors and environmental factors and the post-fire debris flow, the quantitative research on the post-fire debris flow initiation and movement processes, the mechanistic model of post-fire debris flow, and the rapid and efficient control countermeasures of post-fire debris flow.
Rathbone, Alasdair Timothy Llewelyn; Tharmaradinam, Surejini; Jiang, Shucui; Rathbone, Michel P; Kumbhare, Dinesh A
2015-05-01
Post-concussion syndrome is an aggregate of symptoms that commonly present together after head injury. These symptoms, depending on definition, include headaches, dizziness, neuropsychiatric symptoms, and cognitive impairment. However, these symptoms are common, occurring frequently in non-head injured controls, leading some to question the existence of post-concussion syndrome as a unique syndrome. Therefore, some have attempted to explain post-concussion symptoms as post-traumatic stress disorder, as they share many similar symptoms and post-traumatic stress disorder does not require head injury. This explanation falls short as patients with post-concussion syndrome do not necessarily experience many key symptoms of post-traumatic stress disorder. Therefore, other explanations must be sought to explain the prevalence of post-concussion like symptoms in non-head injury patients. Many of the situations in which post-concussion syndrome like symptoms may be experienced such as infection and post-surgery are associated with systemic inflammatory responses, and even neuroinflammation. Post-concussion syndrome itself has a significant neuroinflammatory component. In this review we examine the evidence of neuroinflammation in post-concussion syndrome and the potential role systemic inflammation plays in post-concussion syndrome like symptoms. We conclude that given the overlap between these conditions and the role of inflammation in their etiologies, a new term, post-inflammatory brain syndromes (PIBS), is necessary to describe the common outcomes of many different inflammatory insults. The concept of post-concussion syndrome is in its evolution therefore, the new term post-inflammatory brain syndromes provides a better understanding of etiology of its wide-array of symptoms and the wide array of conditions they can be seen in. Copyright © 2015 Elsevier Inc. All rights reserved.
Comparison of two techniques for removing fiber posts.
Gesi, A; Magnolfi, S; Goracci, C; Ferrari, M
2003-09-01
The purpose of this study was to evaluate the time needed to remove several types of fiber posts using two different bur kits. Estimates refer to the time needed to pass the fiber post until arriving at the gutta-percha. Sixty extracted anterior teeth were treated endodontically. A post space with a standard depth of 10 mm was prepared in each root canal. The sample was randomly divided into 3 groups of 20 specimens each. Three different types of posts were cemented: group 1, Conic 6% tapered fiber posts (Ghimas); group 2, FRC Poster fiber posts (Ivoclar-Vivadent); and group 3, Composipost carbon fiber posts (RTD). To remove the post, for half of each group's specimens the burs from the RTD fiber posts removal kit were used (subgroup A). From the other half of the teeth in each group (subgroup B), posts were removed by using a diamond bur and a Largo bur. Composipost carbon fiber posts (group 3) took significantly less time to remove than the other two types of posts (p < 0.05). For the bur kits, the procedure involving the use of a diamond and a Largo bur (subgroup B) was significantly faster (p < 0.05). The interaction between the type of post and the type of bur kit used was not significant (p > 0.05).
Wang, Vivian J-J; Chen, Ya-Ming; Yip, Kevin H-K; Smales, Roger J; Meng, Qing-Fei; Chen, Lijuan
2008-03-01
To investigate regional root canal push-out bond strengths for two fiber-reinforced post types using two adhesive systems. The crowns of 24 recently extracted sound maxillary central incisors were sectioned transversely 2 mm coronal to the labial cemento-enamel junction, and the roots treated endodontically. Following standardized post space preparations, fiber-reinforced posts (C-POST; AESTHETI-PLUS) were placed using two adhesive systems (acid-etch ONE-STEP PLUS/C&B CEMENT; self-adhesive RelyX Unicem), in four equal groups. Push-out bond strength tests were performed at four sites in each root. Results were analyzed using split-plot ANOVA, with a=0.05 for statistical significance. AESTHETI-PLUS quartz fiber-reinforced posts showed significantly higher push-out strengths than C-POST carbon fiber-reinforced posts (P<0.0001). The separate acid-etch adhesive system resulted in significantly higher bond strengths than the self-etch self-adhesive system (P<0.0001). Bond strengths decreased significantly from coronal to apical root canal regions (P<0.0001). The quartz fiber-reinforced post placed using the separate acid-etch adhesive system provided significantly better post retention than the carbon fiber-reinforced post placed using the self-etch self-adhesive system.
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 postal...
The effect of friction in the hold down post spherical bearings on hold down post loads
NASA Technical Reports Server (NTRS)
Richardson, James A.
1990-01-01
The effect of friction at the connection of the Solid Rocket Booster (SRB) aft skirt and the mobile launch platform (MLP) hold down posts was analyzed. A simplified model of the shuttle response during the Space Shuttle Main Engine (SSME) buildup was constructed. The model included the effect of stick-slip friction for the rotation of the skirt about the spherical bearing. Current finite element models assume the joint is completely frictionless in rotation and therefore no moment is transferred between the skirt and the hold down posts. The model was partially verified against test data and preliminary parameter studies were performed. The parameter studies indicated that the coefficient of friction strongly influenced the moment on the hold down posts. The coefficient of friction had little effect on hold down post vertical loads, however. Further calibration of the model is necessary before the effect of friction on the hold down post horizontal loads can be analyzed.
43 CFR 35.36 - Post-hearing briefs.
Code of Federal Regulations, 2011 CFR
2011-10-01
... CLAIMS AND STATEMENTS § 35.36 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief. The ALJ shall fix the time for filing such... 43 Public Lands: Interior 1 2011-10-01 2011-10-01 false Post-hearing briefs. 35.36 Section 35.36...
29 CFR 22.36 - Post-hearing briefs.
Code of Federal Regulations, 2014 CFR
2014-07-01
... 29 Labor 1 2014-07-01 2013-07-01 true Post-hearing briefs. 22.36 Section 22.36 Labor Office of the Secretary of Labor PROGRAM FRAUD CIVIL REMEDIES ACT OF 1986 § 22.36 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief. The...
43 CFR 35.36 - Post-hearing briefs.
Code of Federal Regulations, 2010 CFR
2010-10-01
... CLAIMS AND STATEMENTS § 35.36 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief. The ALJ shall fix the time for filing such... 43 Public Lands: Interior 1 2010-10-01 2010-10-01 false Post-hearing briefs. 35.36 Section 35.36...
22 CFR 521.36 - Post-hearing briefs.
Code of Federal Regulations, 2010 CFR
2010-04-01
... § 521.36 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief. The ALJ shall fix the time for filing briefs, at a time not... 22 Foreign Relations 2 2010-04-01 2010-04-01 true Post-hearing briefs. 521.36 Section 521.36...
22 CFR 521.36 - Post-hearing briefs.
Code of Federal Regulations, 2011 CFR
2011-04-01
... § 521.36 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief. The ALJ shall fix the time for filing briefs, at a time not... 22 Foreign Relations 2 2011-04-01 2009-04-01 true Post-hearing briefs. 521.36 Section 521.36...
22 CFR 224.36 - Post-hearing briefs.
Code of Federal Regulations, 2012 CFR
2012-04-01
... ACT § 224.36 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief. The ALJ shall fix the time for filing briefs, at a time... 22 Foreign Relations 1 2012-04-01 2012-04-01 false Post-hearing briefs. 224.36 Section 224.36...
22 CFR 521.36 - Post-hearing briefs.
Code of Federal Regulations, 2013 CFR
2013-04-01
... § 521.36 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief. The ALJ shall fix the time for filing briefs, at a time not... 22 Foreign Relations 2 2013-04-01 2009-04-01 true Post-hearing briefs. 521.36 Section 521.36...
22 CFR 224.36 - Post-hearing briefs.
Code of Federal Regulations, 2013 CFR
2013-04-01
... ACT § 224.36 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief. The ALJ shall fix the time for filing briefs, at a time... 22 Foreign Relations 1 2013-04-01 2013-04-01 false Post-hearing briefs. 224.36 Section 224.36...
22 CFR 224.36 - Post-hearing briefs.
Code of Federal Regulations, 2014 CFR
2014-04-01
... ACT § 224.36 Post-hearing briefs. The ALJ may require the parties to file post-hearing briefs. In any event, any party may file a post-hearing brief. The ALJ shall fix the time for filing briefs, at a time... 22 Foreign Relations 1 2014-04-01 2014-04-01 false Post-hearing briefs. 224.36 Section 224.36...