Human megakaryocytes: finding the root

In this issue of Blood, Miyawaki et al identify the most primitive progenitor cell population that makes only megakaryocytes and platelets in adult humans and show it is expanded in myeloproliferative neoplasms such as essential thrombocythemia (ET).1 Approximately 1011 platelets are produced on a daily basis in humans, but their exact journey from undifferentiated hematopoietic stem cells (HSCs) is still highly debated. Platelets have the shortest half-life of all blood components and are rapidly recruited when injury occurs, yet have long been thought to be among the cell types to be specified as the furthest from the HSCs in the hematopoietic hierarchy. For several decades, it was understood that differentiation proceeds by a series of binary fates choices, in particular with a common myeloid progenitor (CMP) downstream of HSCs that would give rise to a restricted myeloid progenitor (granulocyte-macrophage progenitor) and to a megakaryocyte-erythrocyte progenitor (MEP). Only downstream of MEPs would unilineage megakaryocyte and unilineage erythrocyte progenitors arise. Recently though, several groups have reported that megakaryocyte and platelet production may not follow this strict hierarchical branching path. Instead, committed megakaryocyte precursors could be found much earlier, either within the HSC2-4 or the multipotent progenitor compartment.5 An early precursor that exclusively produces human megakaryocytes in humans, however, had not been described.</jats:p

Molecular landscapes of human hematopoietic stem cells in health and leukemia.

Blood cells are organized as a hierarchy with hematopoietic stem cells (HSCs) at the root. The advent of genomic technologies has opened the way for global characterization of the molecular landscape of HSCs and their progeny, both in mouse and human models, at the genetic, transcriptomic, epigenetic, and proteomics levels. Here, we outline our current understanding of the molecular programs that govern human HSCs and how dynamic changes occurring during HSC differentiation are necessary for well-regulated blood formation under homeostasis and upon injury. A large body of evidence is accumulating on how the programs of normal hematopoiesis are modified in acute myeloid leukemia, an aggressive adult malignancy driven by leukemic stem cells. We summarize these findings and their clinical implications.The authors would like to thank Emily Calderbank for critical review of the manuscript. Research in EL laboratory is supported by a Wellcome Trust Sir Henry Dale Fellowship and core support grant from the Wellcome Trust and MRC to the Wellcome Trust – Medical Research Council Cambridge Stem Cell Institute.This is the author accepted manuscript. The final version is available from Wiley via http://dx.doi.org/10.1111/nyas.1298

Effects of vanadyl complexes with acetylacetonate derivatives on non-tumor and tumor cell lines

Vanadium has a good therapeutic potential, as several biological effects, but few side effects, have been demonstrated. Evidence suggests that vanadium compounds could represent a new class of non-platinum, metal antitumor agents. In the present study, we aimed to characterize the antiproliferative activities of fluorescent vanadyl complexes with acetylacetonate derivates bearing asymmetric substitutions on the β-dicarbonyl moiety on different cell lines. The effects of fluorescent vanadyl complexes on proliferation and cell cycle modulation in different cell lines were detected by ATP content using the CellTiter-Glo Luminescent Assay and flow cytometry, respectively. Western blotting was performed to assess the modulation of mitogen-activated protein kinases (MAPKs) and relevant proteins. Confocal microscopy revealed that complexes were mainly localized in the cytoplasm, with a diffuse distribution, as in podocyte or a more aggregate conformation, as in the other cell lines. The effects of complexes on cell cycle were studied by cytofluorimetry and Western blot analysis, suggesting that the inhibition of proliferation could be correlated with a block in the G2/M phase of cell cycle and an increase in cdc2 phosphorylation. Complexes modulated mitogen-activated protein kinases (MAPKs) activation in a cell-dependent manner, but MAPK modulation can only partly explain the antiproliferative activity of these complexes. All together our results demonstrate that antiproliferative effects mediated by these compounds are cell type-dependent and involve the cdc2 and MAPKs pathway

X-HESS: a large sample of highly accreting serendipitous AGN under the XMM-Newton microscope

The bulk of X-ray spectroscopic studies of active galactic nuclei (AGN) are focused on local ($z < 0.1$) sources with low-to-moderate ($< 0.3$) Eddington ratio ($\lambda_\mathrm{Edd}$). It is then mandatory to overcome this limitation and improve our understanding of highly accreting AGN. In this work we present the preliminary results from the analysis of a sample of $\sim70$ high-$\lambda_\mathrm{Edd}$ radio-quiet AGN at $0.06 \leq z \leq 3.3$, based on the 10th release of the XMM-Newton serendipitous source catalogue, that we named as XMM-Newton High-Eddington Serendipitous AGN Sample (X-HESS). Almost $\sim35\%$ of the X-HESS AGN have multi-epoch archival observations and $\sim70\%$ of the sources can rely on simultaneous OM optical data. First results reveal sources showing signatures of ultra-fast outflows and remarkable long- and short-term X-ray flux variations. Indeed in J095847.88+690532.7 ($z \sim 1.3$), one of the most densely monitored objects hosting a $\sim$$10^9\,M_\odot$ supermassive black hole, we discovered a variation of the soft X-ray flux by a factor of > 2 over approximately one week (rest-frame). Large variations in the power-law continuum photon index $\Gamma$ are also observed, questioning expectations from previously reported $\Gamma - \lambda_\mathrm{Edd}$ relations, for which $\Gamma \geq 2$ would be a ubiquitous hallmark of AGN with $\lambda_\mathrm{Edd} \sim 1$.Comment: 7 pages, 5 figures, proceedings of the XMM-Newton Workshop 2022 "Black hole accretion under the X-ray microscope". Accepted for publication in Astronomische Nachrichte

Biodegradable and drug-eluting inorganic composites based on mesoporous zinc oxide for urinary stent applications

Conventional technologies for ureteral stent fabrication suffer from major inconveniences such as the development of encrustations and bacteria biofilm formation. These drawbacks typically lead to the failure of the device, significant patient discomfort and an additional surgery to remove and replace the stent in the worst cases. This work focuses on the preparation of a new nanocomposite material able to show drug elution properties, biodegradation and eventually potential antibacterial activity. Poly(2-hydroxyethyl methacrylate) or the crosslinked poly(2-hydroxyethyl methacrylate)-co-poly(acrylic acid) hydrogels were prepared by the radical polymerization method and combined with a biodegradable and antibacterial filling agent, i.e., flower-like Zinc Oxide (ZnO) micropowders obtained via the hydrothermal route. The physico-chemical analyses revealed the correct incorporation of ZnO within the hydrogel matrix and its highly mesoporous structure and surface area, ideal for drug incorporation. Two different anti-inflammatory drugs (Ibuprofen and Diclofenac) were loaded within each composite and the release profile was monitored up to two weeks in artificial urine (AU) and even at different pH values in AU to simulate pathological conditions. The addition of mesoporous ZnO micropowders to the hydrogel did not negatively affect the drug loading properties of the hydrogel and it was successfully allowed to mitigate undesirable burst-release effects. Furthermore, the sustained release of the drugs over time was observed at neutral pH, with kinetic constants (k) as low as 0.05 h-1. By exploiting the pH-tunable swelling properties of the hydrogel, an even more sustained release was achieved in acidic and alkaline conditions especially at short release times, with a further reduction of burst effects (k ≈ 0.01-0.02 h-1). The nanocomposite system herein proposed represents a new material formulation for preparing innovative drug eluting stents with intrinsic antibacterial properties

Long-Term Safety of Anti-TNF Adalimumab in HBc Antibody-Positive Psoriatic Arthritis Patients: A Retrospective Case Series of 8 Patients

Immunosuppressive drugs commonly used in the treatment of psoriatic arthritis make patients more susceptible to viral, bacterial, and fungal infections because of their mechanism of action. They not only increase the risk of new infections but also act altering the natural course of preexisting infections. While numerous data regarding the reactivation of tuberculosis infection are available in the literature, poor information about the risk of reactivation or exacerbation of hepatitis viruses B and C infections during treatment with biologics has been reported. Furthermore, reported series with biological therapy included short periods of followup, and therefore, they are not adequate to verify the risk of reactivation in the long-term treatment. Our study evaluated patients with a history of hepatitis B and psoriatic arthritis treated with adalimumab and monitored up to six years. During the observation period, treatment was effective and well tolerated in all patients, and liver function tests and viral load levels remained unchanged

Comparative study of the biological behaviour in hamster of two isolates of leishmania characterized respectively as L. major-like and L. donovani

Hamster inoculated intraperitoneally with 1 x 10(7) parasites of L. donovani and L. major-like of the New World were studied in groups of 15, 30, 60 and 90 days of infection. The parasite load and density showed progressive increase with the evolution of the infection and was higher in the L. donovani groups than in the L. major-like groups. The L. major-like groups showed parasite density higher in the spleen than in the liver and was similar in both organs in L. donovani groups. The histopathology showed a diffuse marked hyperplasia and hypertrophy of the reticuloendothelial system with high parasitism in the L. donovani groups while there was focal involvement of these organs in L. major-like groups, forming nodules of macrophages that were scantly parasitised. The biological behaviour could be useful in the preliminary studies of Leishmania strain in regional laboratories and understanding the histopathology of lesions caused by different leishmania species.Experimentos utilizando-se hamsters inoculados intraperitonealmente com 1 x 10(7) parasitas de 2 cepas, L. donovani (MHOM/BR/72/LD 46) e L. major-like (MCAN/BR/73/LD 70) isoladas no Novo Mundo foram realizados e estudados em grupos de 15, 30, 60 e 90 dias de infecção. A carga e a densidade parasitária mostraram progressivo aumento com a evolução da infecção e foi maior nos grupos inoculados com L. donovani do que nos grupos inoculados com L. major-like. Os grupos inoculados com L. major-like mostraram densidade parasitária maior no baço que no fígado e foram semelhantes em ambos os órgãos nos grupos inoculados com L. donovani. A histopatologia mostrou intensa e difusa hyperplasia e hipertrofia do sistema reticuloendotelial com alto parasitismo nos grupos inoculados com L. donovani, enquanto foi encontrado envolvimento focai nestes órgãos nos grupos inoculados com L. major-like, formando nódulos de macrófagos discretamente parasitados. O comportamento biológico seria útil em estudos preliminares de identificação de cepas de Leishmania em laboratórios regionais e na compreensão da histopatologia das lesões causadas por diferentes espécimes de leishmanias