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Exome sequencing identified RPS15A as a novel causative gene for Diamond-Blackfan anemia.
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Exome sequencing identified RPS15A as a novel causative gene for Diamond-Blackfan anemia.

Haematologica. 2016 Dec 01;:

Authors: Ikeda F, Yoshida K, Toki T, Uechi T, Ishida S, Nakajima Y, Sasahara Y, Okuno Y, Kanezaki R, Terui K, Kamio T, Kobayashi A, Fujita T, Sato-Otsubo A, Shiraishi Y, Tanaka H, Chiba K, Muramatsu H, Kanno H, Ohga S, Ohara A, Kojima S, Kenmochi N, Miyano S, Ogawa S, Ito E

PMID: 27909223 [PubMed - as supplied by publisher]




Associations between environmental factors and hospital admissions for sickle cell disease.
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Associations between environmental factors and hospital admissions for sickle cell disease.

Haematologica. 2016 Dec 01;:

Authors: Piel FB, Tewari S, Brousse V, Analitis A, Font A, Menzel S, Chakravorty S, Thein SL, Inusa B, Telfer P, de Montalembert M, Fuller GW, Katsouyanni K, Rees DC

Abstract
Sickle cell disease (SCD) is an increasing global health burden. This inherited disease is characterised by a remarkable phenotypic heterogeneity, which can only partly be explained by genetic factors. Environmental factors are likely to play an important role but studies of their impact on disease severity are limited and their results are often inconsistent. This study investigated associations between a range of environmental factors and hospital admissions of young patients with SCD in London and in Paris between 2008 and 2012. Specific analyses were conducted for sub-groups of patients with different genotypes and for the main reasons of admissions. Generalized additive models and distributed lag non-linear models were used to assess the magnitude of the associations and to calculate relative risks. Some environmental factors significantly influence the numbers of hospital admissions of children with SCD, although the associations identified are complicated. Our study suggests that meteorological factors are more likely to be associated with hospital admissions for SCD than air pollutants. It confirms previous reports of risks associated with wind speed (RR: 1.06/SD [95% confidence interval (CI): 1.00-1.12]) and also with rainfall (RR: 1.06/SD [95%CI: 1.01-1.12]). Maximum atmospheric pressure was found to be a protective factor (RR: 0.93/SD [95%CI: 0.88-0.99]). Weak or no associations were found with temperature. Divergent associations were identified for different genotypes or reasons of admissions, which could partly explain the lack of consistency in earlier studies. Advice to patients with SCD usually includes avoiding a range of environmental conditions that are believed to trigger acute complications, including extreme temperatures and high altitudes. Scientific evidence to support such advice is limited and sometimes confusing. This study shows that environmental factors do explain some of the variations in rates of admission to hospital with acute symptoms in SCD, but the associations are complex, and likely to be specific to different environments and the individual's exposure to them. Furthermore, this study highlights the need for prospective studies with large numbers of patients and standardised protocols across Europe.

PMID: 27909222 [PubMed - as supplied by publisher]




Factors related to diffuse large B-cell lymphoma relative survival in a population-based study in France: is there a role of socio-economic status?
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Factors related to diffuse large B-cell lymphoma relative survival in a population-based study in France: is there a role of socio-economic status?

Haematologica. 2016 Dec 01;:

Authors: Le Guyader-Peyrou S, Orazio S, Dejardin O, Maynadie M, Troussard X, Monnereau A

Abstract
Due to addition of anti-CD20 to anthracycline-based chemotherapy, survival of diffuse large B-cell lymphoma increased during the last decade. Although these trends are encouraging, there are still persistent differences in survival within and between US and European countries suggesting the role of non-biological factors. Our aim was to investigate the influence of such factors on relative survival of diffuse large B-cell lymphoma patients. We conducted a retrospective multicenter registry-based study in France, between 2002 and 2008, on 1165 incident cases of diffuse large B-cell lymphoma Relative survival analyses were performed and data missing were controlled with multiple imputation method. In a multivariate analysis adjusted for age, sex and International prognostic index, we confirmed that time period was associated with a better 5-year relative survival. The registry area, the medical speciality of the care department (onco-hematology versus other), the travel time to the nearest teaching hospital, the place of treatment (teaching versus not-teaching hospital - borderline significance), a comorbidity burden and marital status were independently associated with the 5-year relative survival. Adjusted for first course treatment, inclusion in clinical trial and treatment discussion in multidisciplinary meeting were strongly associated with a better survival outcome. In contrast, the socio-economic status (European Deprivation Index) was not associated with the outcome. Despite therapeutics advances, various non-biological factors affected the relative survival of diffuse large B-cell lymphoma patients. The notion of lymphoma-specific expertise seems to be essential to achieve optimal care management and reopen the debate of centralization of these patients care in hematology/oncology departments.

PMID: 27909221 [PubMed - as supplied by publisher]




Role of serum free light chain assay in the detection of early relapse and prediction of prognosis after relapse in multiple myeloma patients treated upfront with novel agents.
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Role of serum free light chain assay in the detection of early relapse and prediction of prognosis after relapse in multiple myeloma patients treated upfront with novel agents.

Haematologica. 2016 Dec 01;:

Authors: Tacchetti P, Pezzi A, Zamagni E, Pantani L, Rocchi S, Zannetti BA, Mancuso K, Rizzello I, Cavo M

PMID: 27909220 [PubMed - as supplied by publisher]




Superior survival of ex vivo cultured human reticulocytes following transfusion into mice.
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Superior survival of ex vivo cultured human reticulocytes following transfusion into mice.

Haematologica. 2016 Dec 01;:

Authors: Kupzig S, Parsons SF, Curnow E, Anstee DJ, Blair A

Abstract
The generation of cultured red blood cells from stem cell sources may fill an unmet clinical need for transfusion dependent patients, particularly in countries that lack a sufficient and safe blood supply. Cultured red blood cells were generated from human CD34+ cells from adult peripheral blood or cord blood by ex vivo expansion and a comprehensive in vivo survival comparison with standard red cell concentrates was undertaken. Significant amplification (>105 fold) was achieved using CD34+ cells from both cord blood and peripheral blood, generating high yields of enucleated cultured red blood cells. Following transfusion, higher levels of cultured red cells could be detected in the murine circulation compared to standard adult red cells. The proportions of cultured blood cells from cord or peripheral blood sources remained high 24 hours post transfusion (82+/-5% and 78+/-9%, respectively), while standard adult blood cells declined rapidly to only 49+/-9% by this time. In addition, the survival time of cultured blood cells in mice was longer than that of standard adult red cells. A paired comparison of cultured blood cells and standard adult red blood cells from the same donor confirmed the enhanced in vivo survival capacity of the cultured cells. This study represents the first demonstration that ex vivo generated cultured red blood cells survive longer than donor red cells using an in vivo model that more closely mimics clinical transfusion. Cultured red blood cells may offer advantages for transfusion dependent patients by reducing the number of transfusions required.

PMID: 27909219 [PubMed - as supplied by publisher]




Erythrocyte survival is controlled by microRNA-142.
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Erythrocyte survival is controlled by microRNA-142.

Haematologica. 2016 Dec 01;:

Authors: Rivkin N, Chapnik E, Mildner A, Barshtein G, Porat Z, Kartvelishvily E, Dadosh T, Birger Y, Amir G, Yedgar S, Izraeli S, Jung S, Hornstein E

Abstract
Hematopoietic-specific miR-142 is critical regulator of various blood cell lineages, but its role in erythrocytes is unexplored. Here, we characterize miR-142 impact on erythrocyte physiology and molecular cell biology, using a mouse loss of function allele. We report that miR-142 is required for maintaining the typical erythrocyte biconcave shape and structural resilience, for normal metabolism of reactive oxygen species (ROS) and for overall lifespan. miR-142 further controls actin filament homeostasis and membrane skeleton organization. The analyses presented reveal previously-unappreciated functions of miR-142 and contribute to an emerging new view of the pivotal roles played by small RNAs in erythropoiesis. Finally, the work demonstrates how a house-keeping network of cytoskeletal regulators can be reshaped by a single miRNA denominator in a cell type specific manner.

PMID: 27909218 [PubMed - as supplied by publisher]




The small FOXP1 isoform predominantly expressed in activated B cell-like diffuse large B-cell lymphoma and full length FOXP1 exert similar oncogenic and transcriptional activity in human B cells.
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The small FOXP1 isoform predominantly expressed in activated B cell-like diffuse large B-cell lymphoma and full length FOXP1 exert similar oncogenic and transcriptional activity in human B cells.

Haematologica. 2016 Dec 01;:

Authors: van Keimpema M, Grüneberg LJ, Schilder-Tol EJ, Oud ME, Beuling E, Hensbergen PJ, de Jong J, Pals ST, Spaargaren M

Abstract
The forkhead transcription factor FOXP1 is generally regarded as an oncogene in activated B cell-like diffuse large B-cell lymphoma. Previous studies have suggested that a small isoform of FOXP1 (FOXP1-iso), rather than full-length FOXP1 (FOXP1-FL), may possess this oncogenic activity. Corroborating those studies, we here show that activated B cell-like diffuse large B-cell lymphoma cell-lines and primary activated B cell-like diffuse large B-cell lymphoma cells predominantly express FOXP1-iso and that the 5-end of the Foxp1 gene is a common insertion site in murine lymphomas in leukaemia virus- and transposon-mediated insertional mutagenesis screens. By combined mass-spectrometry, (q)RT-PCR/sequencing, and siRNA-mediated gene-silencing, we determined that FOXP1-iso predominantly expressed in activated B cell-like diffuse large B-cell lymphoma lacks the N-terminal 100 amino acids of FOXP1-FL. Aberrant overexpression of FOXP1-iso (ΔN100) in primary human B cells revealed its oncogenic capacity: it repressed apoptosis and plasma cell differentiation. However, no difference in potency was found between FOXP1-iso and FOXP1-FL. Furthermore, overexpression of FOXP1-FL or FOXP1-iso in primary B cells and diffuse large B-cell lymphoma cell-lines resulted in similar gene regulation. Taken together, our data indicate that FOXP1-iso and FOXP1-FL have comparable oncogenic and transcriptional activity, suggesting that aberrant (over)expression of FOXP1, irrespective of the specific isoform, contributes to lymphomagenesis. These novel insights further enhance the value of FOXP1 for the diagnostics, prognostics, and treatment of diffuse large B-cell lymphoma patients.

PMID: 27909217 [PubMed - as supplied by publisher]




Molecular determinants of pathogenesis and clinical phenotype in myeloproliferative neoplasms.
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Molecular determinants of pathogenesis and clinical phenotype in myeloproliferative neoplasms.

Haematologica. 2016 Dec 01;:

Authors: Grinfeld J, Nangalia J, Green AR

Abstract
The myeloproliferative neoplasms are a heterogeneous group of clonal disorders characterised by overproduction of mature cells in the peripheral blood, together with an increased risk of thrombosis and progression to acute myeloid leukemia. The majority of patients with Philadelphia-chromosome negative myeloproliferative neoplasms harbour somatic mutations in Janus kinase 2, leading to constitutive activation. Acquired mutations in calreticulin or myeloproliferative leukemia virus oncogene are found in a significant number of patients with essential thrombocythaemia or myelofibrosis, and mutations in numerous epigenetic regulators and spliceosome components are also seen. Although the cellular and molecular consequences of many of these mutations remain unclear, it seems likely that they interact with germline and microenvironmental factors to influence disease pathogenesis. This review will focus on the determinants of specific myeloproliferative neoplasm phenotypes as well as how an improved understanding of molecular mechanisms can inform our understanding of the disease entities themselves.

PMID: 27909216 [PubMed - as supplied by publisher]




Cure for thalassemia major: from allogeneic hematopoietic stem cell transplantation to gene therapy.
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Cure for thalassemia major: from allogeneic hematopoietic stem cell transplantation to gene therapy.

Haematologica. 2016 Dec 01;:

Authors: Srivastava A, Shaji RV

Abstract
Allogeneic hematopoietic stem cell transplantation has been established for several decades as a gene replacement therapy for patients with thalassemia major and now offers very high rates of cure to those who are able to access this therapy. Outcomes have improved tremendously over the last decade even in high-risk patients. The limited data available suggests that the long-term outcome is also excellent with >90% survival but for best results, hematopoietic stem cell transplantation should be offered early before any end organ damage occurs. However, access to this therapy is limited by lack of suitable donors in more than half the patients. Inadequate hematopoietic stem cell transplantation services and the cost of therapy are other reasons for the same, particularly in those parts of the world which have a high prevalence of this condition. As a result <10% of eligible patients are actuallyable to avail this therapy. Other options for curative therapies are therefore needed. Recently, gene correction in autologous hematopoietic stem cells has been successfully established using lentiviral vectors, and several clinical trials have been initiated. A gene editing approach to correct the β globin mutation or disrupt BCL11A to increase fetal hemoglobin production has also been reported and is expected to be introduced in clinical trials soon. Curative possibilities for the major hemoglobin disorders are expanding. Providing access to these therapies around the world would be the challenge.

PMID: 27909215 [PubMed - as supplied by publisher]




Is ruxolitinib a potentially useful drug in hematological malignancies with RAS pathway hyperactivation?
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Is ruxolitinib a potentially useful drug in hematological malignancies with RAS pathway hyperactivation?

Haematologica. 2016 Dec;101(12):e492

Authors: Geissler K, Jäger E, Barna A, Sliwa T, Knöbl P, Schwarzinger I, Gisslinger H, Valent P

PMID: 27903714 [PubMed - in process]




'Trained immunity': consequences for lymphoid malignancies.
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'Trained immunity': consequences for lymphoid malignancies.

Haematologica. 2016 Dec;101(12):1460-1468

Authors: Stevens WB, Netea MG, Kater AP, van der Velden WJ

Abstract
In hematological malignancies complex interactions exist between the immune system, microorganisms and malignant cells. On one hand, microorganisms can induce cancer, as illustrated by specific infection-induced lymphoproliferative diseases such as Helicobacter pylori-associated gastric mucosa-associated lymphoid tissue lymphoma. On the other hand, malignant cells create an immunosuppressive environment for their own benefit, but this also results in an increased risk of infections. Disrupted innate immunity contributes to the neoplastic transformation of blood cells by several mechanisms, including the uncontrolled clearance of microbial and autoantigens resulting in chronic immune stimulation and proliferation, chronic inflammation, and defective immune surveillance and anti-cancer immunity. Restoring dysfunction or enhancing responsiveness of the innate immune system might therefore represent a new angle for the prevention and treatment of hematological malignancies, in particular lymphoid malignancies and associated infections. Recently, it has been shown that cells of the innate immune system, such as monocytes/macrophages and natural killer cells, harbor features of immunological memory and display enhanced functionality long-term after stimulation with certain microorganisms and vaccines. These functional changes rely on epigenetic reprogramming and have been termed 'trained immunity'. In this review the concept of 'trained immunity' is discussed in the setting of lymphoid malignancies. Amelioration of infectious complications and hematological disease progression can be envisioned to result from the induction of trained immunity, but future studies are required to prove this exciting new hypothesis.

PMID: 27903713 [PubMed - in process]




The myeloma stem cell concept, revisited: from phenomenology to operational terms.
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The myeloma stem cell concept, revisited: from phenomenology to operational terms.

Haematologica. 2016 Dec;101(12):1451-1459

Authors: Johnsen HE, Bøgsted M, Schmitz A, Bødker JS, El-Galaly TC, Johansen P, Valent P, Zojer N, Van Valckenborgh E, Vanderkerken K, van Duin M, Sonneveld P, Perez-Andres M, Orfao A, Dybkær K

Abstract
The concept of the myeloma stem cell may have important therapeutic implications, yet its demonstration has been hampered by a lack of consistency in terms and definitions. Here, we summarize the current documentation and propose single-cell in vitro studies for future translational studies. By the classical approach, a CD19(-)/CD45(low/-)/CD38(high)/CD138(+) malignant plasma cell, but not the CD19(+)/CD38(low/-) memory B cell compartment, is enriched for tumorigenic cells that initiate myeloma in xenografted immunodeficient mice, supporting that myeloma stem cells are present in the malignant PC compartment. Using a new approach, analysis of c-DNA libraries from CD19(+)/CD27(+)/CD38(-) single cells has identified clonotypic memory B cell, suggested to be the cell of origin. This is consistent with multiple myeloma being a multistep hierarchical process before or during clinical presentation. We anticipate that further characterization will require single cell geno- and phenotyping combined with clonogenic assays. To implement such technologies, we propose a revision of the concept of a myeloma stem cell by including operational in vitro assays to describe the cellular components of origin, initiation, maintenance, and evolution of multiple myeloma. These terms are in accordance with recent (2012) consensus statements on the definitions, assays, and nomenclature of cancer stem cells, which is technically precise without completely abolishing established terminology. We expect that this operational model will be useful for future reporting of parameters used to identify and characterize the multiple myeloma stem cells. We strongly recommend that these parameters include validated standard technologies, reproducible assays, and, most importantly, supervised prospective sampling of selected biomaterial which reflects clinical stages, disease spectrum, and therapeutic outcome. This framework is key to the characterization of the cellular architecture of multiple myeloma and its use in precision medicine.

PMID: 27903712 [PubMed - in process]




Ibrutinib in the real world patient: many lights and some shades.
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Ibrutinib in the real world patient: many lights and some shades.

Haematologica. 2016 Dec;101(12):1448-1450

Authors: Ghia P, Cuneo A

PMID: 27903711 [PubMed - in process]




The Hippo-p53 pathway in megakaryopoiesis.
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The Hippo-p53 pathway in megakaryopoiesis.

Haematologica. 2016 Dec;101(12):1446-1448

Authors: Suraneni PK, Crispino JD

PMID: 27903710 [PubMed - in process]




Eltrombopag, a potent stimulator of megakaryopoiesis.
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Eltrombopag, a potent stimulator of megakaryopoiesis.

Haematologica. 2016 Dec;101(12):1443-1445

Authors: Raslova H, Vainchenker W, Plo I

PMID: 27903709 [PubMed - in process]