Haemostasis patterns in patients with acute-on-chronic liver failure and acute decompensation of cirrhosis including thromboelastometric tests with and without the addition of Protac: a pilot study.

BACKGROUND: Thromboelastometry is considered the best method to assesses hemostasis in liver disease. Diagnostic performance could be improved by adding protein C activators such as thrombomodulin or Protac®. We assessed changes in ROTEM parameters after the addition of Protac® in patients with acute-on-chronic liver failure (ACLF), acute decompensation (AD), and healthy individuals (HI) to define different hemostasis patterns, considering standard and velocity ROTEM parameters, and assess whether Protac® can improve the definition of the pattern. METHODS: Pre-test, we investigated whether diluted EXTEM reagent improved the effect of Protac® on the clotting time (CT)-ratio with and without Protac®. Ten ACLF and 20 AD patients and 21 HI were included in the main study. RESULTS: Standard EXTEM was used in the main study. INTEM CFT, INTEM A5 (inverse), and INTEM TPI (inverse) were the parameters that best differentiated liver disease from HI (ROC AUC, 0.921, 0.906, and 0.928, respectively; all P-values < 0.001). Combining INTEM CFT with EXTEM LI60-ratio only slightly improved the diagnostic performance (ROC AUC, 0.948; P < 0.001). EXTEM LI60 and INTEM maxV-t were the parameters that best differentiated between ACLF and AD patients (ROC AUC, 0.743, P = 0.033; and 0.723, P = 0.050; respectively). Combining EXTEM LI60 + INTEM maxV-t moderately improved the diagnostic performance (ROC AUC, 0.81, P < 0.001). CONCLUSIONS: ROTEM velocity, fibrinolysis parameters and the indices calculated improve the diagnosis in combination with standard parameters (e.g., CFT and A5). Ratios calculated with and without Protac® (e.g., EXTEM LI60-ratio) only slightly increased the diagnostic performance in discriminating hemostasis patterns.

Understanding the Effects of Binders in Gas Sorption and Acidity of Aluminium Fumarate Extrudates.

Understanding the impact of shaping processes on solid adsorbents is critical for the implementation of MOFs in industrial separation processes or as catalytic materials. Production of MOF-containing shaped particles is typically associated with loss of porosity and modification of acid sites, two phenomena that affect their performance. Herein, we report a detailed study on how extrusion affects the crystallinity, porosity, and acidity of the aluminium fumarate MOF with clays or SiO2 gel binders. Thorough characterization showed that the clay binders confer the extrudates a good mechanical robustness at the expense of porosity, while silica gel shows an opposite trend. The CO2 selectivity towards CH4 , of interest for natural gas separation processes, is maintained upon the extrusion process. Moreover, probe FTIR spectroscopy revealed no major changes in the types of acid sites. This study highlights that these abundant and inexpensive clay materials may be used for scaling MOFs as active adsorbents.

Visualizing defects and pore connectivity within metal-organic frameworks by X-ray transmission tomography.

Metal-Organic Frameworks (MOFs) have the potential to change the landscape of molecular separations in chemical processes owing to their ability of selectively binding molecules. Their molecular sorting properties generally rely on the micro- and meso-pore structure, as well as on the presence of coordinatively unsaturated sites that interact with the different chemical species present in the feed. In this work, we show a first-of-its-kind tomographic imaging of the crystal morphology of a metal-organic framework by means of transmission X-ray microscopy (TXM), including a detailed data reconstruction and processing approach. Corroboration with Focused Ion Beam-Scanning Electron Microscopy (FIB-SEM) images shows the potential of this strategy for further (non-destructively) assessing the inner architecture of MOF crystals. By doing this, we have unraveled the presence of large voids in the internal structure of a MIL-47(V) crystal, which are typically thought of as rather homogeneous lattices. This challenges the established opinion that hydrothermal syntheses yield relatively defect-free material and sheds further light on the internal morphology of crystals.

Influence of Pore Structure and Metal-Node Geometry on the Polymerization of Ethylene over Cr-Based Metal-Organic Frameworks.

Metal-organic frameworks (MOFs) have received increasing interest as solid single-site catalysts, owing to their tunable pore architecture and metal node geometry. The ability to exploit these modulators makes them prominent candidates for producing polyethylene (PE) materials with narrow dispersity index (Ð) values. Here a study is presented in which the ethylene polymerization properties, with Et2 AlCl as activator, of three renowned Cr-based MOFs, MIL-101(Cr)-NDC (NDC=2,6-dicarboxynapthalene), MIL-53(Cr) and HKUST-1(Cr), are systematically investigated. Ethylene polymerization reactions revealed varying catalytic activities, with MIL-101(Cr)-NDC and MIL-53(Cr) being significantly more active than HKUST-1(Cr). Analysis of the PE products revealed large Ð values, demonstrating that polymerization occurs over a multitude of active Cr centers rather than a singular type of Cr site. Spectroscopic experiments, in the form of powder X-ray diffraction (pXRD), UV/Vis-NIR diffuse reflectance spectroscopy (DRS) and CO probe molecule Fourier transform infrared (FTIR) spectroscopy corroborated these findings, indicating that indeed for each MOF unique active sites are generated, however without alteration of the original oxidation state. Furthermore, the pXRD experiments indicated that one major prerequisite for catalytic activity was the degree of MOF activation by the Et2 AlCl co-catalyst, with the more active materials portraying a larger degree of activation.

Successful management of three patients with autoimmune thrombotic thrombocytopenic purpura with paradigm-changing therapy: Caplacizumab, steroids, plasma exchange, rituximab, and intravenous immunoglobulins (CASPERI).

Autoimmune thrombotic thrombocytopenic purpura (aTTP) is a severe disease caused by the production of autoantibodies against von Willebrand factor (vWF)-cleaving ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin-1 motifs; 13th member of the family). In 2018, caplacizumab was approved for the treatment of patients with acute aTTP in conjunction with plasma exchange (PE) and immunosuppressive therapy. Immunosuppressive standard of care includes mainly steroids whereas rituximab is usually reserved for refractory cases. We report three patients with a first acute episode of aTTP who were successfully treated with a paradigm-changing scheme including standard of care (caplacizumab, steroids and PE) plus upfront therapy with rituximab and intravenous immunoglobulins (CASPERI). Rituximab was added 1-4 days after diagnosis, when ADAMTS13 autoantibodies were detected and intravenous immunoglobulins were administered after performing PE using albumin as replacement solution. Successful outcome was observed in all three patients: platelet recovery (>150 × 109/L) was observed after 3, 4, and 5 days from diagnosis; ADAMTS13 activity >5% and ADAMTS13 autoantibodies were negative after 14, 15, and 21 days from diagnosis. In conclusion, caplacizumab, steroids, PE (using fresh frozen plasma or albumin as replacement solution and adding intravenous immunoglobulins) plus upfront rituximab therapy was a safe and efficient combination to induce remission in case of acute aTTP.

Histamine receptor 1 is expressed in leukaemic cells and affects differentiation sensitivity.

Despite the success of immunotherapy in several haematological neoplasms, the effectiveness in acute myeloid leukaemia (AML) is still controversial, partially due to the lack of knowledge regarding immune-related processes in this disease and similar neoplasias. In this study, we analysed the role and expression of histamine receptor 1 (HRH1) in haematological malignancies. Although the histamine receptor type 1 was widely expressed in healthy and malignant haematopoiesis, especially along the myeloid lineage, HRH1 lacked a relevant role in survival/proliferation and chemoresistance of AML cells, as analysed by HRH1 knockdown (KD) and pharmacological modulation. However, HRH1-mediated signalling was critical for the activation of the differentiation process induced by several agents including all-trans retinoic acid, establishing a role for HRH1 in myeloid differentiation. Pharmacological activation of Erk was able to partially restore differentiation capacity in HRH1 KD AML cells, suggesting that HRH1 signalling acts upstream MAPK-Erk pathway. As an indirect consequence of our results, treatment-related histamine release is not expected to confer a proliferative advantage in leukaemic cells.

Spectroscopy, microscopy, diffraction and scattering of archetypal MOFs: formation, metal sites in catalysis and thin films.

Metal-organic frameworks (MOFs) are a class of porous crystalline materials showing great potential for applications such as catalysis, gas storage, molecular separations, energy storage and drug delivery. The properties that render them interesting stem from their structure (e.g. morphology, porosity or metal coordination and geometry). Thus, gaining a deeper understanding strongly relies on the availability and adequate use of advanced characterization tools, which can interrogate MOFs under realistic synthesis as well as catalysis (or sorption) conditions. Herein, we present an overview of the various characterization techniques specifically suitable for the study on the underlying chemistry of the formation mechanisms and adsorption properties of three archetypal MOFs, namely MIL-100, ZIF-8 and HKUST-1. A section on using MOFs as supports for metal atoms or complexes that can be used for catalysis on the robust Zr6 nodes of UiO-66 or NU-1000, and the characterization techniques used thereof, is presented as well. In addition, we discuss recent developments on the application of nano-spectroscopic characterization for MOF thin-films and explore the potential of MOFs as model systems in catalysis. The conclusions and outlook provide future research possibilities in the field of MOF characterization.

In Situ Spectroscopy of Calcium Fluoride Anchored Metal-Organic Framework Thin Films during Gas Sorption.

Surface-mounted metal-organic frameworks (SURMOFs) show promising behavior for a manifold of applications. As MOF thin films are often unsuitable for conventional characterization techniques, understanding their advantageous properties over their bulk counterparts presents a great analytical challenge. In this work, we demonstrate that MOFs can be grown on calcium fluoride (CaF2 ) windows after proper functionalization. As CaF2 is optically (in the IR and UV/Vis range of the spectrum) transparent, this makes it possible to study SURMOFs using conventional spectroscopic tools typically used during catalysis or gas sorption. Hence, we have measured HKUST-1 during the adsorption of CO and NO. We show that no copper oxide impurities are observed and also confirm that SURMOFs grown by a layer-by-layer (LbL) approach possess Cu+ species in paddlewheel confirmation, but 1.9 times less than in bulk HKUST-1. The developed methodology paves the way for studying the interaction of any adsorbed gases with thin films, not limited to MOFs, low temperatures, or these specific probe molecules, pushing the boundaries of our current understanding of functional porous materials.

Correction: Micro-spectroscopy of HKUST-1 metal-organic framework crystals loaded with tetracyanoquinodimethane: effects of water on host-guest chemistry and electrical conductivity.

Correction for 'Micro-spectroscopy of HKUST-1 metal-organic framework crystals loaded with tetracyanoquinodimethane: effects of water on host-guest chemistry and electrical conductivity' by Miguel Rivera-Torrente et al., Phys. Chem. Chem. Phys., 2019, 21, 25678-25689.

Multi-Spectroscopic Interrogation of the Spatial Linker Distribution in Defect-Engineered Metal-Organic Framework Crystals: The [Cu3 (btc)2-x (cydc)x ] Showcase.

In the past few years, defect-engineered metal-organic frameworks (DEMOFs) have been studied due to the plethora of textural, catalytic, or magnetic properties that can be enhanced by carefully introducing defect sites into the crystal lattices of MOFs. In this work, the spatial distribution of two different non-defective and defective linkers, namely 1,3,5-benzenetricarboxylate (BTC) and 5-cyano-1,3-benzenedicarboxylate (CYDC), respectively, has been studied in different DEMOF crystals of the HKUST-1 topology. Raman micro-spectroscopy revealed a nonhomogeneous distribution of defect sites within the [Cu3 (btc)2-x (cydc)x ] crystals, with the CYDC linker incorporated into defect-rich or defect-free areas of selected crystals. Additionally, advanced bulk techniques have shed light on the nature of the copper species, which is highly dynamic and directly affects the reactivity of the copper sites, as shown by probe molecule FTIR spectroscopy. Furthermore, electron microscopy revealed the effect of co-crystallizing CYDC and BTC on the crystal size and the formation of mesopores, further corroborated by X-ray scattering analysis. In this way we have demonstrated the necessity of utilizing micro-spectroscopy along with a whole array of bulk spectroscopic techniques to fully describe multicomponent metal-organic frameworks.

Nanoweb Surface-Mounted Metal-Organic Framework Films with Tunable Amounts of Acid Sites as Tailored Catalysts.

Metal-organic frameworks (MOFs) are a promising class of materials for many applications, due to their high chemical tunability and superb porosity. By growing MOFs as (thin-)films, additional properties and potential applications become available. Here, copper (II) 1,3,5-benzenetricarboxylate (Cu-BTC) metal-organic framework (MOF) thin-films are reported, which were synthesized by spin-coating, resulting in "nanowebs", that is, fiber-like structures. These surface-mounted MOFs (SURMOFs) were studied by using photoinduced force microscopy (PiFM) and time-of-flight secondary ion mass spectrometry (ToF-SIMS). The optimal concentration of precursors (10 mm) was determined that resulted in chemically homogeneous, pure nanowebs. Furthermore, the morphology and (un)coordinated Cu sites in the web were tuned by varying the rotation speed of the spin-coating process. X-ray diffraction (XRD) analysis showed that rotation speeds ≥2000 rpm (with precursors in a water/ethanol solution) generate the catena-triaqua-µ-(1,3,5-benzenetricarboxylate)-copper(II), or Cu(BTC)(H2 O)3 coordination polymer. X-ray photoelectron spectroscopy (XPS) highlighted the strong decrease in number of (defective) Cu+ sites, as the nanowebs mainly consist of coordinated Cu2+ Lewis acid sites (LAS) and organic linker-linker, for example, hydrogen-bonding, interactions. Finally, the Lewis-acidic character of the Cu sites is illustrated by testing the films as catalysts in the isomerization of α-pinene oxide. The higher number of LAS (≥3000 rpm), result in higher campholenic aldehyde selectivity reaching up to 87.7 %. Furthermore, the strength of a combined micro- and spectroscopic approach in understanding the nature of MOF thin-films in a spatially resolved manner is highlighted.

Micro-spectroscopy of HKUST-1 metal-organic framework crystals loaded with tetracyanoquinodimethane: effects of water on host-guest chemistry and electrical conductivity.

Composite materials, consisting of a metal-organic framework (MOF) and a guest molecule, further denoted as guest@MOF composites, have gained strong interest due to the guest-induced tunability of the host properties, for example in sensing or electroconductivity applications. However, decoding the complexity of these guest@MOF composites and extracting structure-performance relationships are far from trivial and require the use of a gamut of characterization tools. In this work, we use various micro-spectroscopic tools both under static (ex situ) and dynamic (in situ) conditions to map the properties and diffusion behavior of TCNQ (7,7,8,8-tetracyanoquinodimethane) as a guest molecule in single HKUST-1 crystals as the host. Raman micro-spectroscopy allowed us to map the spatial distribution of TCNQ within HKUST-1 single crystals, thereby revealing a heterogeneous distribution of TCNQ after initial TCNQ-infiltration, concentrated at the crystal edges, and a homogeneous redistribution upon water vapor treatment. These insights are correlated to I-V scans at different temperatures and to electrochemical impedance spectroscopy (EIS), which allowed us to verify the different contributions to conductivity. These data showed changes in electrical conductivity after exposing the sample to moisture and air. In situ FT-IR micro-spectroscopy during treatment with moisturized nitrogen gas suggests lower transient diffusion rates for water inside TCNQ@HKUST-1 relative to pristine HKUST-1, likely due to steric hindrance of the pore-filling TCNQ molecules in the HKUST-1 framework. The application of micro-spectroscopic techniques is crucial to uncovering MOF intracrystal heterogeneities and yielding rationally-derived instructions for the improved design of guest@MOF systems.

Dual lysosomal-mitochondrial targeting by antihistamines to eradicate leukaemic cells.

BACKGROUND: Despite great efforts to identify druggable molecular targets for AML, there remains an unmet need for more effective therapies. METHODS: An in silico screening was performed using Connectivity Maps to identify FDA-approved drugs that may revert an early leukaemic transformation gene signature. Hit compounds were validated in AML cell lines. Cytotoxic effects were assessed both in primary AML patient samples and healthy donor blood cells. Xenotransplantation assays were undertaken to determine the effect on engraftment of hit compounds. The mechanism of action responsible for the antileukaemic effect was studied focussing on lysosomes and mitochondria. FINDINGS: We identified a group of antihistamines (termed ANHAs) with distinct physicochemical properties associated with their cationic-amphiphilic nature, that selectively killed leukaemic cells. ANHAs behaved as antileukaemic agents against primary AML samples ex vivo, sparing healthy cells. Moreover, ANHAs severely impaired the in vivo leukaemia regeneration capacity. ANHAs' cytotoxicity relied on simultaneous mitochondrial and lysosomal disruption and induction of autophagy and apoptosis. The pharmacological effect was exerted based on their physicochemical properties that permitted the passive targeting of both organelles, without the involvement of active molecular recognition. INTERPRETATION: Dual targeting of lysosomes and mitochondria constitutes a new promising therapeutic approach for leukaemia treatment, supporting the further clinical development. FUND: This work was funded by the Fundación Mutua Madrileña (RMR), CaixaImpulse (RMR), the Spanish Ministry of Economy (RMR), the Josep Carreras International Leukaemia Foundation (RMR), l'Obra Social "La Caixa" (RMR), and Generalitat de Catalunya (IJC).

Serotonin receptor type 1B constitutes a therapeutic target for MDS and CMML.

Myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) are chronic myeloid clonal neoplasms. To date, the only potentially curative therapy for these disorders remains allogeneic hematopoietic progenitor cell transplantation (HCT), although patient eligibility is limited due to high morbimortality associated with this procedure coupled with advanced age of most patients. Dopamine receptors (DRs) and serotonin receptors type 1 (HTR1s) were identified as cancer stem cell therapeutic targets in acute myeloid leukemia. Given their close pathophysiologic relationship, expression of HTR1s and DRs was interrogated in MDS and CMML. Both receptors were differentially expressed in patient samples compared to healthy donors. Treatment with HTR1B antagonists reduced cell viability. HTR1 antagonists showed a synergistic cytotoxic effect with currently approved hypomethylating agents in AML cells. Our results suggest that HTR1B constitutes a novel therapeutic target for MDS and CMML. Due to its druggability, the clinical development of new regimens based on this target is promising.

Metal-Organic Frameworks as Catalyst Supports: Influence of Lattice Disorder on Metal Nanoparticle Formation.

Because of their high tunability and surface area, metal-organic frameworks (MOFs) show great promise as supports for metal nanoparticles. Depending on the synthesis route, MOFs may contain defects. Here, we show that highly crystalline MIL-100(Fe) and disordered Basolite® F300, with identical iron 1,3,5-benzenetricarboxylate composition, exhibit very divergent properties when used as a support for Pd nanoparticle deposition. While MIL-100(Fe) shows a regular MTN-zeotype crystal structure with two types of cages, Basolite® F300 lacks long-range order beyond 8 Šand has a single-pore system. The medium-range configurational linker-node disorder in Basolite® F300 results in a reduced number of Lewis acid sites, yielding more hydrophobic surface properties compared to hydrophilic MIL-100(Fe). The hydrophilic/hydrophobic nature of MIL-100(Fe) and Basolite® F300 impacts the amount of Pd and particle size distribution of Pd nanoparticles deposited during colloidal synthesis and dry impregnation methods, respectively. It is suggested that polar (apolar) solvents/precursors attractively interact with hydrophilic (hydrophobic) MOF surfaces, allowing tools at hand to increase the level of control over, for example, the nanoparticle size distribution.

Clinico-biological characteristics and outcome of hepatitis C virus-positive patients with diffuse large B-cell lymphoma treated with immunochemotherapy.

Diffuse large B cell lymphoma (DLBCL) patients carrying hepatitis C virus (HCV) have higher risk of treatment toxicity and complications. The aim of this study was to assess the impact of HCV in a series of DLBCL patients treated with immunochemotherapy. 321 patients (161 M/160F; median age, 66 years) diagnosed with de novo DLBCL in a single center between 2002 and 2013 were included. Immunodeficiency-related lymphomas were excluded. HCV+ cases were defined by the presence of IgG anti-HCV. Main clinico-biological characteristics and outcome were analyzed according to the viral status. Two hundred ninety patients were HCV- and 31 HCV+. HCV+ patients were older (median age 71 vs. 64 years, P = 0.03), had more often B symptoms (P = 0.013), spleen (P = 0.003), and liver (P = 0.011) involvement, higher rate of early death (<4 months, P = .001), and shorter overall survival (OS). Eleven HCV+ patients had cirrhosis criteria. HCV+ patients with impaired liver function before or during treatment showed inferior OS. Elevated pre-treatment bilirubin correlated also with higher liver toxicity. In a multivariate analysis that included R-IPI score, serum beta2-microglobulin (ß2m), HCV status, and presence of cirrhosis, only R-IPI, ß2m, and cirrhosis showed independent prognostic impact on OS. The presence of HCV in DLBCL patients entails higher number of complications and early deaths; however, liver impairment and not the hepatitis viral status was the key feature in the outcome of the patients.

Repositioning of bromocriptine for treatment of acute myeloid leukemia.

BACKGROUND: Treatment for acute myeloid leukemia (AML) has not significantly changed in the last decades and new therapeutic approaches are needed to achieve prolonged survival rates. Leukemia stem cells (LSC) are responsible for the initiation and maintenance of AML due to their stem-cell properties. Differentiation therapies aim to abrogate the self-renewal capacity and diminish blast lifespan. METHODS: An in silico screening was designed to search for FDA-approved small molecules that potentially induce differentiation of AML cells. Bromocriptine was identified and validated in an in vitro screening. Bromocriptine is an approved drug originally indicated for Parkinson's disease, acromegaly, hyperprolactinemia and galactorrhoea, and recently repositioned for diabetes mellitus. RESULTS: Treatment with bromocriptine reduced cell viability of AML cells by activation of the apoptosis program and induction of myeloid differentiation. Moreover, the LSC-enriched primitive AML cell fraction was more sensitive to the presence of bromocriptine. In fact, bromocriptine decreased the clonogenic capacity of AML cells. Interestingly, a negligible effect is observed in healthy blood cells and hematopoietic stem/progenitor cells. CONCLUSIONS: Our results support the use of bromocriptine as an anti-AML drug in a repositioning setting and the further clinical validation of this preclinical study.

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Static electromagnetic field effects on pineal vesicles: a morphological and morphometric study in chick embryos / Efectos de un campo magnético estático sobre las vesículas pineales: estudio morfológico y morfométrico en embriones de pollo

The effects of static electromagnetic field exposure on the development of pineal cell aggregates were studied in chick embryos. Static electromagnetic fields were created by a solenoidal coil (110×160 mm) kept inside the incubators and connected to a power supply. The magnetic field generated was static and uniform (frequency = 0; wavelength = 0) and the intensities were 18 mT and 36 mT. Eggs were incubated either under control or static electromagnetic field conditions, and embryos were sacrificed after 5, 10 and 15 days of incubation. The morphology, number and density of pineal aggregates were determined in three pineal areas (apical, anterior and posterior). In exposed embryos, the vesicles appeared earlier (by the 5th day) and after 15 days of incubation the number of vesicles was higher and stroma compaction was greater than in controls. These changes in vesicle morphology and density suggest that a static electromagnetic field might be able to stimulate pineal maturation and development in the chick embryo (AU)

Se investigaron los efectos de la exposición a un campo magnético estático sobre el desarrollo de agregaciones de células pineales en embriones de pollo. Los campos electromagnéticos estáticos fueron creados utilizando un resorte solenoidal (110 x 160 mm) mantenido dentro de las incubadoras y conectado a una fuente eléctrica. El campo magnético así generado era estático y uniforme (frecuencia = 0; longitud de onda = 0) y las intensidades eran de 18 mT y 36 mT. Los huevos fueron incubados bajo condiciones bien de control bien de campo electromagnético y los embriones fueron sacrificados a los días 5, 10 y 15 de incubación. La morfología, número y densidad de agregaciones pineales fueron determinados en tres áreas de la glándula pineal (apical, anterior y posterior). En los embriones expuestos, las vesículas aparecieron antes (antes del día 5) y a los 15 días de incubación el número de vesículas era mayor y el grado de compactación del estroma era mayor que en los controles. Estos cambios en la morfología y en la densidad de las vesículas sugieren que un campo magnético estático quizá pueda estimular la maduración y desarrollo de los embriones de pollo (AU)