Library consortia in Germany

Whenever German librarians talk about consortia in the presence of lawyers (even if they are libarians themselves) they meet with vehement protest. In German the legal term „consortium“ is restricted to a relatively narrow meaning. In „Meyers neues Lexikon“ from 1993 it is defined as: „Bank merger for stock exchange dealings and credit transactions ...“ And from the same source the definition of consortial business: „Syndicate business for which several members (mostly banks) join up for a consortium. Reasons for forming a consortium are: 1. Overstraining of the financial resources of each individual consortium member, 2. spreading of risks ...“ 1 While risk-spreading is not really an issue for libraries, their financial resources are undoubtedly overstrained. There are three reasons: the pricing policy – that is to say the heavy annual price rise – of the publishers, the rapidly increasing number of academic publications not likely to slow down in the foreseeable future as well as the expectations and wishes of our users and customers, the scientific community. Therefore, the term „purchasing association“ may be the correct one from a (German) legal point of view. As in many similar cases the term was adopted from an Anglo-American background with a much broader meaning: „Partnership, association. Now more specifically an association of business, banking or manufacturing organizations.“ 2 In Germany the term „consortium“ is now widely used for joint actions of libraries

JAK2 Inhibition: Reviewing a New Therapeutical Option in Myeloproliferative Neoplasms

JAK2 is a tyrosine kinase gene that plays an essential role in the development of normal haematopoiesis. Hyperactivation of JAK2 occurs in myeloproliferative neoplasms by different mechanisms. As a consequence, JAK2 inhibitors have been designed to suppress the cytokine signalling cascade caused by the constitutive activation of JAK2. In clinical trials, JAK2 inhibitors are efficient in decreasing spleen size, controlling clinical symptoms, and improving quality of life in patients with myeloproliferative neoplasms. However, JAK2 inhibitors are unable to target uncommitted hematopoietic progenitors responsible of the initiation of the myeloproliferative disease. It is expected that, in order to cure the myeloproliferative disease, JAK2 inhibitors should be combined with other drugs to target simultaneously different pathways and to target the initiator hematopoietic cell population in myeloproliferative disorders. Taking advantage of the inhibition of the cytokine cascade of JAK2 inhibitors, these compounds are going to be used not only to treat patients with hematological neoplasms but may also be beneficial to treat patients with rheumatoid arthritis or other inflammatory diseases

Plasticity of Cell Migration in Vivo and in Silico

Cell migration results from stepwise mechanical and chemical interactions between cells and their extracellular environment. Mechanistic principles that determine single-cell and collective migration modes and their interconversions depend upon the polarization, adhesion, deformability, contractility, and proteolytic ability of cells. Cellular determinants of cell migration respond to extracellular cues, including tissue composition, topography, alignment, and tissue-associated growth factors and cytokines. Both cellular determinants and tissue determinants are interdependent; undergo reciprocal adjustment; and jointly impact cell decision making, navigation, and migration outcome in complex environments. We here review the variability, decision making, and adaptation of cell migration approached by live-cell, in vivo, and in silico strategies, with a focus on cell movements in morphogenesis, repair, immune surveillance, and cancer metastasi

Identification and Modulation of Drug Resistance in Acute Myeloid Leukemia

A continuous, strictly organised process of blood cell production or hematopoiesis normally takes place in the bone marrow. The human hematopoietic system is capable of replacing the normal daily loss of peripheral blood cells, and will adapt the blood cell formation to increased demands such as bleeding or infection. This system is capable of maintaining a balance between cell loss and formation. The different types of blood cells that are normally present in the peripheral blood, are derived from committed progenitor cells. The compartment of these committed progenitor cells is maintained by a small population of pluripotent stem cells. Besides the ability of the stem cells to give rise to committed progenitor cells, they are capable of self-renewal. The process of proliferation and differentiation is regulated by cellular interaction, i.e. the microenvironment in the bone marrow, and several regulatory glycoproteins, the hematopoietic growth factors (HGPs). Malignant transformation of hematopoietic cells somewhere during their development and leading to the accumulation of immature hemopoietic cells is referred to as leukemia. According to the clinical presentation, the leukemias are divided in acute and chronic leukemias. Acute leukemias, if untreated, will lead to death within several weeks or months, while patients with untreated chronic leukemias often may survive for several years. Depending on the cell lineages involved, a further distinction in myeloid or lymphoid leukemias can be made. In this thesis, acute myeloid leukemia is subject of investigation

Reversal of typical multidrug resistance by cyclosporin and its non-immunosuppressive analogue SDZ PSC 833 in Chinese hamster ovary cells expressing the mdr1 phenotype

Summary The new non-immunosuppressive cyclosporin derivative SDZ PSC 833 (PSC) is a potent agent used to overcome typical multidrug resistance (MDR) associated with overexpression of themdr1 gene encoding for a P-170 glycoprotein. In the present study, the efficacy of PSC as compared with cyclosporin was determined in Chinese hamster ovary cell lines exhibiting different levels of resistance to colchicine (0, 0.1, 0.2 and 10 μg/ml, respectively). Low concentrations of PSC (8.2nm) increased the cytotoxicity of colchicine in cell lines expressing low levels of drug resistance. The concentration resulting in 50% cell survival (LC50 value) found for colchicine alone or in combination with PSC in the CHO-A3 cell line that was resistant to 100 ng colchicine/ml decreased from >500 to 200 ng/ml at 8.2nm PSC and to 500 ng/ml for colchicine alone to 500 ng/ml for colchicine used in combination with 8.2nm PSC and to <100 ng/ml for colchicine combined with 82 or 820nm PSC. At a concentration of 82nm PSC, the maximal effect in MDR reversal was observed in the cell lines exhibiting moderate resistance. In the highly resistant cell line, PSC (820nm) also reversed colchicine resistance. In drug-accumulation experiments, we obtained a 4-fold increase in intracellular doxorubicin accumulation using 820nm PSC. A comparison of PSC with cyclosporin revealed that a cyclosporin concentration 20-fold that of PSC was required to obtain the same sensitising effect. On the basis of these data, it may be concluded that PSC is a most promising chemosensitiser

Reduced corticosteroid use in adult patients with primary immune thrombocytopenia receiving romiplostim

Adult patients with primary immune thrombocytopenia requiring first-line treatment typically receive corticosteroids, which are associated with low response rates and many potential side effects. In a retrospective analysis of two 6-month, placebo-controlled, phase III trials, corticosteroid use decreased from 30 to 26% among patients treated with the novel thrombopoietin-mimetic romiplostim (n = 83) and remained above 30% for placebo-treated patients (n = 42). Moreover, compared to placebo, patients were spared 7 weeks of corticosteroid treatment for every 100 weeks of romiplostim treatment. Thereafter, corticosteroid use continued to decrease significantly, from 35 to 20%, in patients treated with romiplostim for up to 3 years in an open-label extension study (n = 101), and patients were spared a further 8 weeks of corticosteroid treatment for each additional 100 weeks of romiplostim treatment. Such reductions in corticosteroids may improve health-related quality of life in patients with primary immune thrombocytopenia

Measuring Mitochondrial Oxygen Tension during Red Blood Cell Transfusion in Chronic Anemia Patients:A Pilot Study

In light of the associated risks, the question has been raised whether the decision to give a blood transfusion should solely be based on the hemoglobin level. As mitochondria are the final destination of oxygen transport, mitochondrial parameters are suggested to be of added value. The aims of this pilot study were to investigate the effect of a red blood cell transfusion on mitochondrial oxygenation as measured by the COMET device in chronic anemia patients and to explore the clinical usability of the COMET monitor in blood transfusion treatments, especially the feasibility of performing measurements in an outpatient setting. To correct the effect of volume load on mitochondrial oxygenation, a red blood cell transfusion and a saline infusion were given in random order. In total, 21 patients were included, and this resulted in 31 observations. If patients participated twice, the order of infusion was reversed. In both the measurements wherein a blood transfusion was given first and wherein 500 mL of 0.9% saline was given first, the median mitochondrial oxygen tension decreased after red blood cell transfusion. The results of this study have strengthened the need for further research into the effect of blood transfusion tissue oxygenation and the potential role of mitochondrial parameters herein.</p

COVID-19-associated immune thrombocytopenia

Thrombocytopenia is a risk factor for increased morbidity and mortality in patients with the new severe acute respiratory syndrome corona virus, SARS-CoV-2 infection (COVID-19 infection).1 Thrombocytopenia in COVID-19 patients may be caused by disseminated intravascular coagulation (DIC), sepsis or drug-induced. Recently a single case report suggested immune thrombocytopenia (ITP) may be associated with COVID-19 infection.2 ITP is a rare autoimmune disease characterized by a platelet count < 100x109/L, leading to an increased bleeding risk.3 Several risk factors have been described for ITP including environmental (e.g. infection, malignancy and drugs) and genetic predisposition.4 We report here the first case series of three patients with ITP associated with COVID-19 infection

Comprehensive characterization of circulating tumor cells and cell-free DNA in patients with metastatic melanoma

Advances in therapeutic approaches for melanoma urge the need for biomarkers that can identify patients at risk for recurrence and to guide treatment. The potential use of liquid biopsies in identifying biomarkers is increasingly being recognized. Here, we present a head-to-head comparison of several techniques to analyze circulating tumor cells (CTCs) and cell-free DNA (cfDNA) in 20 patients with metastatic melanoma. In this study, we investigated whether diagnostic leukapheresis (DLA) combined with multimarker flow cytometry (FCM) increased the detection of CTCs in blood compared to the CellSearch platform. Additionally, we characterized cfDNA at the level of somatic mutations, extent of aneuploidy and genome-wide DNA methylation. Both CTCs and cfDNA measures were compared to tumor markers and extracranial tumor burden on radiological imaging. Compared to the CellSearch method applied on peripheral blood, DLA combined with FCM increased the proportion of patients with detectable CTCs from 35% to 70% (P = 0.06). However, the median percentage of cells that could be recovered by the DLA procedure was 29%. Alternatively, cfDNA mutation and methylation analysis detected tumor load in the majority of patients (90% and 93% of samples successfully analyzed, respectively). The aneuploidy score was positive in 35% of all patients. From all tumor measurements in blood, lactate dehydrogenase (LDH) levels were significantly correlated to variant allele frequency (P = 0.004). Furthermore, the presence of CTCs in DLA was associated with tumor burden (P &lt; 0.001), whereas the presence of CTCs in peripheral blood was associated with number of lesions on radiological imaging (P &lt; 0.001). In conclusion, DLA tended to increase the proportion of patients with detectable CTCs but was also associated with low recovery. Both cfDNA and CTCs were correlated with clinical parameters such as LDH levels and extracranial tumor burden.</p