搜索结果：Hematology (Amsterdam, Netherlands)

Vaccination guidelines for patients treated for hematological diseases are typically conservative. Given their high risk for severe COVID-19, it is important to identify those patients that benefit from vaccination. We prospectively quantified serum immunoglobulin G (IgG) antibodies to spike subunit 1 (S1) antigens during and after 2-dose mRNA-1273 (Spikevax/Moderna) vaccination in hematology patients. Obtaining S1 IgG ≥ 300 binding antibody units (BAUs)/mL was considered adequate as it represents the lower level of S1 IgG concentration obtained in healthy individuals, and it correlates with potent virus neutralization. Selected patients (n = 723) were severely immunocompromised owing to their disease or treatment thereof. Nevertheless, >50% of patients obtained S1 IgG ≥ 300 BAUs/mL after 2-dose mRNA-1273. All patients with sickle cell disease or chronic myeloid leukemia obtained adequate antibody concentrations. Around 70% of patients with chronic graft-versus-host disease (cGVHD), multiple myeloma, or untreated chronic lymphocytic leukemia (CLL) obtained S1 IgG ≥ 300 BAUs/mL. Ruxolitinib or hypomethylating therapy but not high-dose chemotherapy blunted responses in myeloid malignancies. Responses in patients with lymphoma, patients with CLL on ibrutinib, and chimeric antigen receptor T-cell recipients were low. The minimal time interval after autologous hematopoietic cell transplantation (HCT) to reach adequate concentrations was <2 months for multiple myeloma, 8 months for lymphoma, and 4 to 6 months after allogeneic HCT. Serum IgG4, absolute B- and natural killer-cell number, and number of immunosuppressants predicted S1 IgG ≥ 300 BAUs/mL. Hematology patients on chemotherapy, shortly after HCT, or with cGVHD should not be precluded from vaccination. This trial was registered at Netherlands Trial Register as #NL9553.

BACKGROUND: Patients with hematological malignancies (HM) are at high risk of mortality from SARS-CoV-2 disease 2019 (COVID-19). A better understanding of risk factors for adverse outcomes may improve clinical management in these patients. We therefore studied baseline characteristics of HM patients developing COVID-19 and analyzed predictors of mortality. METHODS: The survey was supported by the Scientific Working Group Infection in Hematology of the European Hematology Association (EHA). Eligible for the analysis were adult patients with HM and laboratory-confirmed COVID-19 observed between March and December 2020. RESULTS: The study sample includes 3801 cases, represented by lymphoproliferative (mainly non-Hodgkin lymphoma n = 1084, myeloma n = 684 and chronic lymphoid leukemia n = 474) and myeloproliferative malignancies (mainly acute myeloid leukemia n = 497 and myelodysplastic syndromes n = 279). Severe/critical COVID-19 was observed in 63.8% of patients (n = 2425). Overall, 2778 (73.1%) of the patients were hospitalized, 689 (18.1%) of whom were admitted to intensive care units (ICUs). Overall, 1185 patients (31.2%) died. The primary cause of death was COVID-19 in 688 patients (58.1%), HM in 173 patients (14.6%), and a combination of both COVID-19 and progressing HM in 155 patients (13.1%). Highest mortality was observed in acute myeloid leukemia (199/497, 40%) and myelodysplastic syndromes (118/279, 42.3%). The mortality rate significantly decreased between the first COVID-19 wave (March-May 2020) and the second wave (October-December 2020) (581/1427, 40.7% vs. 439/1773, 24.8%, p value < 0.0001). In the multivariable analysis, age, active malignancy, chronic cardiac disease, liver disease, renal impairment, smoking history, and ICU stay correlated with mortality. Acute myeloid leukemia was a higher mortality risk than lymphoproliferative diseases. CONCLUSIONS: This survey confirms that COVID-19 patients with HM are at high risk of lethal complications. However, improved COVID-19 prevention has reduced mortality despite an increase in the number of reported cases.

BACKGROUND: Clinical laboratory reference intervals have not been established in many African countries, and non-local intervals are commonly used in clinical trials to screen and monitor adverse events (AEs) among African participants. Using laboratory reference intervals derived from other populations excludes potential trial volunteers in Africa and makes AE assessment challenging. The objective of this study was to establish clinical laboratory reference intervals for 25 hematology, immunology and biochemistry values among healthy African adults typical of those who might join a clinical trial. METHODS AND FINDINGS: Equal proportions of men and women were invited to participate in a cross sectional study at seven clinical centers (Kigali, Rwanda; Masaka and Entebbe, Uganda; two in Nairobi and one in Kilifi, Kenya; and Lusaka, Zambia). All laboratories used hematology, immunology and biochemistry analyzers validated by an independent clinical laboratory. Clinical and Laboratory Standards Institute guidelines were followed to create study consensus intervals. For comparison, AE grading criteria published by the U.S. National Institute of Allergy and Infectious Diseases Division of AIDS (DAIDS) and other U.S. reference intervals were used. 2,990 potential volunteers were screened, and 2,105 (1,083 men and 1,022 women) were included in the analysis. While some significant gender and regional differences were observed, creating consensus African study intervals from the complete data was possible for 18 of the 25 analytes. Compared to reference intervals from the U.S., we found lower hematocrit and hemoglobin levels, particularly among women, lower white blood cell and neutrophil counts, and lower amylase. Both genders had elevated eosinophil counts, immunoglobulin G, total and direct bilirubin, lactate dehydrogenase and creatine phosphokinase, the latter being more pronounced among women. When graded against U.S. -derived DAIDS AE grading criteria, we observed 774 (35.3%) volunteers with grade one or higher results; 314 (14.9%) had elevated total bilirubin, and 201 (9.6%) had low neutrophil counts. These otherwise healthy volunteers would be excluded or would require special exemption to participate in many clinical trials. CONCLUSIONS: To accelerate clinical trials in Africa, and to improve their scientific validity, locally appropriate reference ranges should be used. This study provides ranges that will inform inclusion criteria and evaluation of adverse events for studies in these regions of Africa.

// Peter Valent 1,2 , Attilio Orazi 3 , David P. Steensma 4 , Benjamin L. Ebert 5 , Detlef Haase 6 , Luca Malcovati 7 , Arjan A. van de Loosdrecht 8 , Torsten Haferlach 9 , Theresia M. Westers 8 , Denise A. Wells 10 , Aristoteles Giagounidis 11 , Michael Loken 10 , Alberto Orfao 12 , Michael L&uuml;bbert 13 , Arnold Ganser 14 , Wolf-Karsten Hofmann 15 , Kiyoyuki Ogata 16 , Julie Schanz 6 , Marie C. B&eacute;n&eacute; 17 , Gregor Hoermann 18 , Wolfgang R. Sperr 1,2 , Karl Sotlar 19 , Peter Bettelheim 20 , Reinhard Stauder 21 , Michael Pfeilst&ouml;cker 22 , Hans-Peter Horny 23 , Ulrich Germing 24 , Peter Greenberg 25 and John M. Bennett 26 1 Department of Internal Medicine I, Division of Hematology &amp; Hemostaseology, Medical University of Vienna, Vienna, Austria 2 Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria 3 Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA 4 Division of Hematological Malignancies, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA 5 Division of Hematology, Department of Medicine, Brigham and Women&rsquo;s Hospital, Harvard Medical School, Boston, MA, USA 6 Clinic of Hematology and Medical Oncology, Universitymedicine G&ouml;ttingen, G&ouml;ttingen, Germany 7 Department of Molecular Medicine, University of Pavia, Pavia, Italy 8 Department of Hematology Cancer Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands 9 Munich Leukemia Laboratory (MLL), Munich, Germany 10 Hematologics, Inc., Seattle, WA, USA 11 Department of Internal Medicine II, Marien Hospital, D&uuml;sseldorf, Germany 12 Servicio Central de Citometr&iacute;a, Centro de Investigaci&oacute;n del C&aacute;ncer (IBMCC, CSIC-USAL) and IBSAL, Universidad de Salamanca, Salamanca, Spain 13 Department of Medicine I, Medical Center-University of Freiburg, Freiburg, Germany 14 Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany 15 Department of Hematology and Oncology, University Hospital Mannheim, Medical Faculty Mannheim of the University of Heidelberg, Mannheim, Germany 16 Metropolitan Research and Treatment Center for Blood Disorders (MRTC Japan), Tokyo, Japan 17 Laboratoire d&rsquo;H&eacute;matologie CHU de Nantes, Nantes, France 18 Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria 19 Institute of Pathology, Paracelsus Medical University Salzburg, Salzburg, Austria 20 Elisabethinen Hospital, Linz, Austria 21 Department of Internal Medicine V (Haematology and Oncology) Innsbruck Medical University, Innsbruck, Austria 22 3rd Medical Department, Hanusch Hospital, Vienna, Austria 23 Institute of Pathology, Ludwig-Maximilians University, Munich, Germany 24 Department of Hematology, Oncology, and Clinical Immunology, Heinrich-Heine-University, D&uuml;sseldorf, Germany 25 Stanford University Cancer Institute, Stanford, CA, USA 26 Department of Pathology, Hematopathology Unit and James P Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA Correspondence to: Peter Valent, email: // Keywords : myelodysplasia, diagnostic criteria, standardization, pre-MDS conditions Received : May 03, 2017 Accepted : June 26, 2017 Published : July 05, 2017 Abstract Myelodysplastic syndromes (MDS) comprise a heterogeneous group of myeloid neoplasms characterized by peripheral cytopenia, dysplasia, and a variable clinical course with about 30% risk to transform to secondary acute myeloid leukemia (AML). In the past 15 years, diagnostic evaluations, prognostication, and treatment of MDS have improved substantially. However, with the discovery of molecular markers and advent of novel targeted therapies, new challenges have emerged in the complex field of MDS. For example, MDS-related molecular lesions may be detectable in healthy individuals and increase in prevalence with age. Other patients exhibit persistent cytopenia of unknown etiology without dysplasia. Although these conditions are potential pre-phases of MDS they may also transform into other bone marrow neoplasms. Recently identified molecular, cytogenetic, and flow-based parameters may add in the delineation and prognostication of these conditions. However, no generally accepted integrated classification and no related criteria are as yet available. In an attempt to address this challenge, an international consensus group discussed these issues in a working conference in July 2016. The outcomes of this conference are summarized in the present article which includes criteria and a proposal for the classification of pre-MDS conditions as well as updated minimal diagnostic criteria of MDS. Moreover, we propose diagnostic standards to delineate between &acute;normal&acute;, pre-MDS, and MDS. These standards and criteria should facilitate diagnostic and prognostic evaluations in clinical studies as well as in clinical practice.

Lead exposure has been linked to health challenges involving multiple organ failure. More than fifty percent of lead present in the human body is accumulated in the liver causing hepatic injury. A major mechanism of lead toxicity is oxidative stress. TrévoTM is a nutritional supplement with numerous bioactive natural products with detoxifying and antioxidant properties. This study was designed to investigate the hepatoprotective effects of TrévoTM dietary supplements against lead-hepatotoxicity in male Wistar rats. Thirty-five healthy animals were divided into five groups of seven each as follows: Group I=control; II=15 mg/kg of lead acetate (PbA); III= 2 mL/kg of TrévoTM + PbA; IV= 5 mL/kg of TrévoTM + PbA;V=5 mL/kg of TrévoTM . Animals were orally treated with TrévoTM for two days before co-administration with PbA intraperitoneally for 12 consecutive days. Animals were sacrificed 24 h after the last administration and blood were collected via cardiac puncture and processed for hematological parameters and assessment of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and albumin (ALB). The liver was excised and processed for markers of oxidative stress and histopathological examination. Intraperitoneal administration of 15 mg/kg of PbA caused a significant increase in serum concentration of AST, ALT, while the concentration of ALB was significantly decreased (Plt;0.001). PbA caused a significant reduction in packed cell volume, hemoglobin while the total white blood cell count, neutrophils, lymphocytes, monocytes, eosinophils, and basophils were increased. Oxidative stress was significantly pronounced in the liver of rats exposed to PbA as observed in the high concentration of malonedialdehyde, decreased concentration of glutathione, the activity of catalase, superoxide dismutase, and glutathione-S-transferase. Pretreatment with TrévoTM was able to significantly prevent the anemic, oxidative damage, and hepatic injury initiated by PbA. Histological examination also corroborated the biochemical results. In conclusion, the study reveals that TrévoTM is effective in attenuating PbA-induced hepatotoxicity in male Wistar rats.

Telomeres are highly dynamic structures that adjust the cellular response to stress and growth stimulation based on previous cell divisions. This critical function is accomplished by progressive telomere shortening and DNA damage responses activated by chromosome ends without sufficient telomere repeats. Repair of critically short telomeres by telomerase or recombination is limited in most somatic cells, and apoptosis or cellular senescence is triggered when too many uncapped telomeres accumulate. The chance of the latter increases as the average telomere length decreases. The average telomere length is set and maintained in cells of the germ line that typically express high levels of telomerase. In somatic cells, the telomere length typically declines with age, posing a barrier to tumor growth but also contributing to loss of cells with age. Loss of (stem) cells via telomere attrition provides strong selection for abnormal cells in which malignant progression is facilitated by genome instability resulting from uncapped telomeres. The critical role of telomeres in cell proliferation and aging is illustrated in patients with 50% of normal telomerase levels resulting from a mutation in one of the telomerase genes. Here, the role of telomeres and telomerase in human biology is reviewed from a personal historical perspective.

24 th Congress of European Hematology Association was held from 13 th to 16 th July in Amsterdam, Netherlands. Over 12000 specialists took part in the meeting and more than 360 oral and 1300 poster presentations were made, covering most of hematology fields. The main purpose of this article was to review the most important and relevant topics discussed during congress in such areas as hematopoietic stem cell transplantation, lymphomas, acute leukemia, multiple myeloma and other plasma cell disorders, myeloproliferative neoplasms and infectious complications in hematological patients.

Fanconi anemia is an inherited disease characterized by congenital malformations, pancytopenia, cancer predisposition, and sensitivity to cross-linking agents. The molecular diagnosis of Fanconi anemia is relatively complex for several aspects including genetic heterogeneity with mutations in at least 16 different genes. In this paper, we report the mutations identified in 100 unrelated probands enrolled into the National Network of the Italian Association of Pediatric Hematoly and Oncology. In approximately half of these cases, mutational screening was carried out after retroviral complementation analyses or protein analysis. In the other half, the analysis was performed on the most frequently mutated genes or using a next generation sequencing approach. We identified 108 distinct variants of the FANCA, FANCG, FANCC, FANCD2, and FANCB genes in 85, 9, 3, 2, and 1 families, respectively. Despite the relatively high number of private mutations, 45 of which are novel Fanconi anemia alleles, 26% of the FANCA alleles are due to 5 distinct mutations. Most of the mutations are large genomic deletions and nonsense or frameshift mutations, although we identified a series of missense mutations, whose pathogenetic role was not always certain. The molecular diagnosis of Fanconi anemia is still a tiered procedure that requires identifying candidate genes to avoid useless sequencing. Introduction of next generation sequencing strategies will greatly improve the diagnostic process, allowing a rapid analysis of all the genes.

For many years, through its dedicated scientific working group and sessions at its Annual Congress, the European Hematology Association (EHA) has underscored the commitment of hematologists to address the issue of Quality of Life of patients affected by hematologic diseases. Understandably, when the

Changes in hematological and serum biochemistry parameters in female zinc (Zn)-dosed farm-raised mallards (Anas platyrhynchos) fed four different diets were examined. Sixty ducks received an average dose of 0.97 g of Zn in the form of eight, 3.30-mm diameter shot pellets containing 98% Zn and 2% tin, and another 60 ducks were sham-dosed as controls. Fifteen ducks from each of the two dosing groups were assigned to one of four dietary treatments: corn only, corn with soil, commercial duck ration only, or commercial duck ration with soil. Shot-pellet dissolution rates ranged from 7 mg/Zn/day to 27 mg/Zn/day. Regardless of diet, the Zn dose resulted in mortality; incoordination; paralysis and anorexia; decreased body, liver, pancreas, gonad, and gizzard weight; increased kidney weight; and macroscopic lesions. Zn-dosed ducks had a lower mean erythrocyte packed cell volume (PCV), higher mean reticulocyte count, and a greater number of individuals with immature and/or abnormal erythrocytes, than did control mallards. Mean total leucocyte counts were higher in Zn-dosed ducks than in controls. Zn-dosed ducks that had soil available had higher leucocyte counts than those without soil. Zn-dosed ducks were characterized by a marked heterophilia and relative lymphopenia. In Zn-dosed ducks, the mean lymphocyte count was highest in those provided a commercial duck ration, and lowest in those fed corn. In control ducks, the mean lymphocyte count was highest in ducks fed corn, and lowest in those provided soil along with a commercial duck ration. Zn-dosed mallards had higher serum aspartate aminotransferase and amylase levels, and lower alkaline phosphatase activities than control ducks. Serum phosphorus and uric acid concentrations were higher, and calcium, glucose, and total protein levels lower, in Zn-dosed ducks than in control ducks. Diet did affect serum calcium, phosphorus, total protein, and uric acid concentrations. Differences in erythrocyte and leucocyte parameters, serum enzyme activities, and metabolite concentrations were associated with dose and diet effects. Diets high in protein and other organic matter and calcium and phosphorus did not prevent or substantially alleviate Zn toxicosis in farm-raised mallard ducks.

The upcoming 5th edition of the World Health Organization (WHO) Classification of Haematolymphoid Tumours is part of an effort to hierarchically catalogue human cancers arising in various organ systems within a single relational database. This paper summarizes the new WHO classification scheme for myeloid and histiocytic/dendritic neoplasms and provides an overview of the principles and rationale underpinning changes from the prior edition. The definition and diagnosis of disease types continues to be based on multiple clinicopathologic parameters, but with refinement of diagnostic criteria and emphasis on therapeutically and/or prognostically actionable biomarkers. While a genetic basis for defining diseases is sought where possible, the classification strives to keep practical worldwide applicability in perspective. The result is an enhanced, contemporary, evidence-based classification of myeloid and histiocytic/dendritic neoplasms, rooted in molecular biology and an organizational structure that permits future scalability as new discoveries continue to inexorably inform future editions.

// Laurens E. Franssen 1 , Inger S. Nijhof 1 , Chad C. Bjorklund 2 , Hsiling Chiu 2 , Ruud Doorn 3 , Jeroen van Velzen 3 , Maarten Emmelot 1 , Berris van Kessel 1 , Mark-David Levin 4 , Gerard M.J. Bos 5 , Annemiek Broijl 6 , Saskia K. Klein 7 , Harry R. Koene 8 , Andries C. Bloem 3 , Aart Beeker 9 , Laura M. Faber 10 , Ellen van der Spek 11 , Reinier Raymakers 12 , Pieter Sonneveld 6 , Sonja Zweegman 1 , Henk M. Lokhorst 1 , Anjan Thakurta 2 , Xiaozhong Qian 2 , Tuna Mutis 1 and Niels W.C.J. van de Donk 1 1 Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands 2 Department of Translational Development, Celgene Corporation, Summit, NJ, USA 3 Laboratory for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands 4 Department of Internal Medicine, Albert Schweitzer Hospital, Dordrecht, The Netherlands 5 Department of Hematology, Maastricht University Medical Center, Maastricht, The Netherlands 6 Department of Hematology, Erasmus Medical Center, Rotterdam, The Netherlands 7 Department of Internal Medicine, Meander Medical Center, Amersfoort, The Netherlands 8 Department of Hematology, St. Antonius Hospital, Nieuwegein, The Netherlands 9 Department of Internal Medicine, Spaarne Hospital, Hoofddorp, The Netherlands 10 Department of Internal Medicine, Rode Kruis Hospital, Beverwijk, The Netherlands 11 Department of Internal Medicine, Rijnstate Hospital, Arnhem, The Netherlands 12 Department of Hematology, University Medical Center Utrecht Cancer Center, Utrecht, The Netherlands Correspondence to: Niels W.C.J. van de Donk, email: n.vandedonk@vumc.nl Keywords: multiple myeloma; immunomodulation; lenalidomide; refractory; cyclophosphamide Received: May 01, 2018&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Accepted: September 10, 2018&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Published: September 21, 2018 ABSTRACT We recently showed that the outcome of multiple myeloma (MM) patients treated in the REPEAT study (evaluation of lenalidomide combined with low-dose cyclophosphamide and prednisone (REP) in lenalidomide-refractory MM) was markedly better than what has been described with cyclophosphamide-prednisone alone. The outcome with REP was not associated with plasma cell Cereblon expression levels, suggesting that the effect of REP treatment may involve mechanisms independent of plasma cell Cereblon-mediated direct anti-tumor activity. We therefore hypothesized that immunomodulatory effects contribute to the anti-MM activity of REP treatment, rather than plasma cell Cereblon-mediated effects. Consequently, we now characterized the effect of REP treatment on immune cell subsets in peripheral blood samples collected on day 1 and 14 of cycle 1, as well as on day 1 of cycle 2. We observed a significant mid-cycle decrease in the Cereblon substrate proteins Ikaros and Aiolos in diverse lymphocyte subsets, which was paralleled by an increase in T-cell activation. These effects were restored to baseline at day one of the second cycle, one week after lenalidomide interruption. In vitro , lenalidomide enhanced peripheral blood mononuclear cell-mediated killing of both lenalidomide-sensitive and lenalidomide-resistant MM cells in a co-culture system. These results indicate that the Cereblon-mediated immunomodulatory properties of lenalidomide are maintained in lenalidomide-refractory MM patients and may contribute to immune-mediated killing of MM cells. Therefore, combining lenalidomide with other drugs can have potent effects through immunomodulation, even in patients considered to be lenalidomide-refractory.

Dannis G. van Vuurden 1 , Esther Hulleman 1 , Olga L.M. Meijer 1 , Laurine E. Wedekind 1 , Marcel Kool 2 , Hendrik Witt 2,3 , W. Peter Vandertop 4 , Thomas W&uuml;rdinger 4,5 , David P. Noske 4 , Gertjan J.L. Kaspers 6 and Jacqueline Cloos 6,7 1 Department of Pediatric Oncology / Hematology, Neuro-oncology Research Group, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands 2 Department of Molecular Genetics of Childhood Brain Tumors, German Cancer Research Center (DKFZ), Heidelberg, Germany 3 Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Germany 4 Departments of Neurosurgery, Neuro-oncology Research Group, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands 5 Molecular Neurogenetics Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA 6 Department of Pediatric Oncology / Hematology, VU University Medical Center, Amsterdam, the Netherlands 7 Department of Hematology, VU University Medical Center, Amsterdam, the Netherlands Received: November 24, 2011; Accepted: December 9, 2011; Published: December 15, 2011; Keywords: PARP, radiation, medulloblastoma, ependymoma, glioma, pediatric Correspondence: Dannis van Vuurden, email: // // Abstract Poly ADP-ribose polymerase (PARP) is a protein involved in single strand break repair.&nbsp; Recently, PARP inhibitors have shown considerable promise in the treatment of several cancers, both in monotherapy and in combination with cytotoxic agents. Synthetic lethal action of PARP inhibitors has been observed in tumors with mutations in double strand break repair pathways. In addition, PARP inhibition potentially enhances sensitivity of tumor cells to DNA damaging agents, including radiotherapy.&nbsp; Aim of this study is to determine the radiosensitizing properties of the PARP inhibitor Olaparib in childhood medulloblastoma, ependymoma and high grade glioma (HGG). Increased PARP1 expression was observed in medulloblastoma, ependymoma and HGG, as compared to non-neoplastic brain tissue. Pediatric high grade glioma, medulloblastoma and ependymoma gene expression profiling revealed that high PARP1 expression is associated with poor prognosis. Cell growth inhibition assays with Olaparib resulted in differential sensitivity, with IC 50 values ranging from 1.4 to 8.4 &micro;M, irrespective of tumor type and PARP1 protein expression. Sensitization to radiation was observed in medulloblastoma, ependymoma and HGG cell lines with subcytotoxic concentrations of Olaparib, which coincided with persistence of double strand breaks. Combining PARP inhibitors with radiotherapy in clinical studies in childhood high grade brain tumors may improve therapeutic outcome.

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.

Extracellular vesicles (EVs), through their complex cargo, can reflect the state of their cell of origin and change the functions and phenotypes of other cells. These features indicate strong biomarker and therapeutic potential and have generated broad interest, as evidenced by the steady year-on-year increase in the numbers of scientific publications about EVs. Important advances have been made in EV metrology and in understanding and applying EV biology. However, hurdles remain to realising the potential of EVs in domains ranging from basic biology to clinical applications due to challenges in EV nomenclature, separation from non-vesicular extracellular particles, characterisation and functional studies. To address the challenges and opportunities in this rapidly evolving field, the International Society for Extracellular Vesicles (ISEV) updates its 'Minimal Information for Studies of Extracellular Vesicles', which was first published in 2014 and then in 2018 as MISEV2014 and MISEV2018, respectively. The goal of the current document, MISEV2023, is to provide researchers with an updated snapshot of available approaches and their advantages and limitations for production, separation and characterisation of EVs from multiple sources, including cell culture, body fluids and solid tissues. In addition to presenting the latest state of the art in basic principles of EV research, this document also covers advanced techniques and approaches that are currently expanding the boundaries of the field. MISEV2023 also includes new sections on EV release and uptake and a brief discussion of in vivo approaches to study EVs. Compiling feedback from ISEV expert task forces and more than 1000 researchers, this document conveys the current state of EV research to facilitate robust scientific discoveries and move the field forward even more rapidly.

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Recent studies revealed that platelets normally gradually loose surface sialic acid as they circulate and age through cleavage by sialidases 1. It has been shown in vitro that desialylation of the platelet von Willebrand Factor Receptor Complex triggers platelet clearance and primes glycoprotein (GP)Ibα and GPV for metalloproteinase dependent cleavage, which could be circumvented with a sialidase inhibitor 2. Immune thrombocytopenia (ITP) is an autoimmune disease characterized by autoantibody-induced platelet destruction, often resulting in mild bleeding symptoms, but may also lead to severe bleeding manifestations such as intracranial hemorrhage 3. Many ITP patients, particularly patients with anti-GP Ib-IX autoantibodies, do not respond to conventional treatments such as steroids, intravenous immunoglobulins, or splenectomy 4-8. Also the role of new therapies like thrombopoietin agonist are unclear and not without risks 9. Oseltamivir phosphate, the ethyl ester prodrug of oseltamivir carboxylate that conventionally serves as an antiviral sialidase inhibitor, has been prescribed worldwide for the treatment of patients with influenza 10. Sporadic case reports showed a significant response on platelet count in patients with chronic ITP who were treated with oseltamivir 6, 11. We hypothesized that oseltamivir treatment leads to an increase in platelet count due to its inhibition of sialidases. To investigate this, we performed a retrospective observational study in consecutive patients from the Erasmus Medical Center, Rotterdam, The Netherlands. From January 2011 till May 2013, a total of 175 patients were prescribed oseltamivir (Tamiflu) because of suspicion of influenza and 204 patients were tested positive for influenza. Patients were divided into patients with oseltamivir treatment with proven influenza (N = 117), and without influenza (N = 58) and patients without oseltamivir with proven influenza (N = 87). Mean age was 52.2, 51.3, and 54.4 years, respectively. The mean amount of days of oseltamivir treatment was 4.3 and 6.0 for patients without and with influenza. Platelet count of 109 patients was available on Day 1: patients with oseltamivir treatment without influenza (N = 24), patients with oseltamivir treatment with influenza (N = 53) and patients with influenza without oseltamivir treatment (N = 32). Figure 1A shows an increase in mean platelet count during treatment with oseltamivir. Although not significant this increase was larger in patients without influenza. After 5 days of treatment, a significant increase in platelet count was found in patients treated with oseltamivir compared to patients who did not use oseltamivir (Fig. 1B). No significant differences were found between patients treated with oseltamivir with and without influenza. A: Platelet count in patients with and without treatment with oseltamivir. A trend to increase in platelet count was found in patients with oseltamivir treatment with and without influenza, but statistical significance was not reached (P > 0.05). Mean and s.e.m. are given. B: Percentage of increase in platelet count 5 days after start of treatment with oseltamivir. Percentage of increase in platelet count 5 days after treatment with oseltamivir in patients with and without influenza and in patients with influenza without oseltamivir treatment. *P < 0.05 compared to patients with influenza without oseltamivir (measured with the non-parametric Mann–Whitney test). This is the first study that investigates the effect of oseltamivir, a sialidase inhibitor, on platelet counts. We found a significant increase in platelet counts in a large cohort of patients who used oseltamivir. This was independent whether influenza was diagnosed, which is in concordance with the positive effects on platelet counts in patients with chronic ITP and influenza. This study is a proof of principle that sialidase inhibition increases platelet count in humans, probably by decreasing clearance of platelets. This might provide a bans for a new treatment option for patients with thrombocytopenia refractory to current treatment regimens. Further (prospective) research is needed to investigate the role of oseltamivir in treatment of patients with thrombocytopenia or platelet transfusion. AJGJ designed and performed research, collected and analyzed data, interpreted results, and wrote the manuscript. JP, HGZ, and MH designed research, interpreted results, and participated in discussions. HN designed research, interpreted results, and assisted in writing the paper. All authors have read and approved the manuscript for submission. Arend Jan Gerard Jansen,1,2* Jun Peng,3,4 Hong-Guo Zhao,5 Ming Hou,3,4 Heyu Ni,6,7,8,9 1Department of Hematology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands; 2Department of Plasma Proteins, Sanquin-AMC Landsteiner Laboratory, Amsterdam, The Netherlands; 3Department of Hematology, Qilu Hospital, Shandong University, Jinan, China; 4Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Jinan, China; 5Department of Hematology, the Affiliated Hospital of Qingdao University Medical College, Qingdao, China; 6Toronto Platelet Immunobiology Group, Toronto, Ontario, Canada; 7Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada; 8Canadian Blood Services; 9Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada

The discovery that lymphocyte subpopulations participate in distinct components of the immune response focused attention onto the origins and function of lymphocytes more than 40 years ago. Studies in the 1960s and 1970s demonstrated that B and T lymphocytes were responsible primarily for the basic functions of antibody production and cell-mediated immune responses, respectively. The decades that followed have witnessed a continuum of unfolding complexities in B-cell development, subsets, and function that could not have been predicted. Some of the landmark discoveries that led to our current understanding of B lymphocytes as the source of protective innate and adaptive antibodies are highlighted in this essay. The phenotypic and functional diversity of B lymphocytes, their regulatory roles independent of antibody production, and the molecular events that make this lineage unique are also considered. Finally, perturbations in B-cell development that give rise to certain types of congenital immunodeficiency, leukemia/lymphoma, and autoimmune disease are discussed in the context of normal B-cell development and selection. Despite the significant advances that have been made at the cellular and molecular levels, there is much more to learn, and cross-disciplinary studies in hematology and immunology will continue to pave the way for new discoveries.

// Lonneke J. Verboon 1 , Askar Obulkasim 1 , Jasmijn D.E. de Rooij 1 , Jenny E. Katsman-Kuipers 1 , Edwin Sonneveld 2 , Andr&eacute; Baruchel 3 , Jan Trka 4 , Dirk Reinhardt 5 , Rob Pieters 6 , Jacqueline Cloos 7 , Gertjan J.L. Kaspers 7 , Jan-Henning Klusmann 8 , Christian Michel Zwaan 1 , Maarten Fornerod 1 , Marry M. van den Heuvel-Eibrink 1, 6 1 Department of Pediatric Oncology, Erasmus MC-Sophia Children&rsquo;s Hospital Rotterdam, Rotterdam, The Netherlands 2 Dutch Childhood Oncology Group (DCOG), The Hague, The Netherlands 3 Department of Hematology, Hopital Saint- Louis, Paris, France 4 Department of Pediatric Hematology/Oncology, 2nd Medical School, Charles University, Prague, Czech Republic 5 Clinic for Pediatrics III, University Hospital Essen, Essen, Germany 6 Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands 7 Paediatric Oncology/Haematology, VU University Medical Centre, Amsterdam, The Netherlands 8 Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany Correspondence to: Marry M. van den Heuvel-Eibrink, email: m.m.vandenheuvel-eibrink@prinsesmaximacentrum.nl Keywords: acute myeloid leukemia, MLL, relapse, miR-106b~25 Received: February 28, 2016&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Accepted: June 08, 2016&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Published: June 24, 2016 ABSTRACT The most important reason for therapy failure in pediatric acute myeloid leukemia (AML) is relapse. In order to identify miRNAs that contribute to the clonal evolution towards relapse in pediatric AML, miRNA expression profiling of 127 de novo pediatric AML cases were used. In the diagnostic phase, no miRNA signatures could be identified that were predictive for relapse occurrence, in a large pediatric cohort, nor in a nested mixed lineage leukemia ( MLL) -rearranged pediatric cohort. AML with MLL - rearrangements are found in 15-20% of all pediatric AML samples, and reveal a relapse rate up to 50% for certain translocation partner subgroups. Therefore, microRNA expression profiling of six paired initial diagnosis-relapse MLL -rearranged pediatric AML samples (test cohort) and additional eight paired initial diagnosis-relapse samples with MLL -rearrangements (validation cohort) was performed. A list of 53 differentially expressed miRNAs was identified of which the miR-106b~25 cluster, located in intron 13 of MCM7 , was the most prominent. These differentially expressed miRNAs however could not predict a relapse in de novo AML samples with MLL -rearrangements at diagnosis. Furthermore, higher mRNA expression of both MCM7 and its upstream regulator E2F1 was found in relapse samples with MLL -rearrangements. In conclusion, we identified the miR-106b~25 cluster to be upregulated in relapse pediatric AML with MLL -rearrangements.