Anti-Endothelial Cell Antibodies are not frequently elevated in hospitalized patients with COVID-19

COVID-19 is now established to be associated with a thrombotic phenomenon, now called COVID-19 associated coagulopathy (CAC). Anti-Endothelial Cell Antibodies (AECA) are a heterogenous group of autoantibodies targeting various endothelial cell antigens or antigens adhering to endothelial cells, They are commonly observed in a variety of auto-immune and rheumatologic conditions, and were observed in patients with the severe acute respiratory syndrome (SARS) in 2005. We aimed to assess AECA status in patients with COVID-19 and their potential contributing role to endothelial injury and CAC. AECA identification was a relatively infrequent finding in COVID-19 patients on admission, and their presence, albeit in only 2/33 patients, was not associated with disease severity. However, as the autoantibodies were only measured at admission, we cannot exclude the possibility of pathogenic AECA developing later in the course of diseaseFurther studies using additional methods are needed to evaluate the presence and potential pathogenic role of AECA in later stages of COVID-19

Dark chocolate modulates platelet function with a mechanism mediated by flavan-3-ol metabolites

Cocoa is a rich source bioactive compounds, i.e., flavan-3-ols, and its consumption has been associated with several beneficial effects, such as the positive modulation of the hemostasis targeted by the platelet function. However, these phenolic compounds have a very low bioavailability and extensively undergo phase I and II metabolism, with the appearing into the bloodstream of (epi) catechin conjugates and phenyl-g-valerolactones and their conjugates, at different times. The aims of this study were to explore the effect of dark chocolate on platelet function and to investigate the relationship between this interplay and flavan-3-ol derived metabolites. Eighteen healthy male volunteers ingested 50 g of 90% cocoa chocolate within 5 minutes. Blood samples were collected immediately before chocolate ingestion (T0) and 4 hours afterwards (T1). Platelet function analyzer (PFA)-100 closure time was assessed using collagen/adenosine-50-diphosphate (COL/ADP) and collagen/epinephrine (COL/EPI) cartridges. Plasma flavan-3-ol metabolites were identified and quantified by means of liquid chromatography coupled to a triple quadrupole mass spectrometer (UHPLC-ESI-MS/MS). Results evidenced a significant increase of COL/ADP-induced PFA-100 closure time, but not COL/EPI, 4 hours after ingestion of dark chocolate. Total plasma structurally-related (epi)catechin metabolite (SREM) concentration significantly increased at T1, together with 4 out of the 6 detected metabolites. Total phenyl-g-valerolactone concentrations remained unchanged. Spearman correlations evidenced a strong correlation between COL/ADP closure time and SREMs, mainly led by (epi)catechin-sulfate isomers. These data confirm that the potential beneficial effect of dark chocolate on primary hemostasis may be mediated by flavan-3-ol circulating metabolites

Long-term survival in multiple myeloma is associated with a distinct immunological profile, which includes proliferative cytotoxic T-cell clones and a favourable Treg/Th17 balance

Despite improved outcomes in multiple myeloma (MM), a cure remains elusive. However, even before the current therapeutic era, 5% of patients survived >10 years and we propose that immune factors contribute to this longer survival. We identified patient

Targeting CD83 in mantle cell lymphoma with anti-human CD83 antibody

Objectives: Effective antibody–drug conjugates (ADCs) provide potent targeted cancer therapies. CD83 is expressed on activated immune cells including B cells and is a therapeutic target for Hodgkin lymphoma. Our objective was to determine CD83 expression on non-Hodgkin lymphoma (NHL) and its therapeutic potential to treat mantle cell lymphoma (MCL) which is currently an incurable NHL. Methods: We analysed CD83 expression on MCL cell lines and the lymph node/bone marrow biopsies of MCL patients. We tested the killing effect of CD83 ADC in vitro and in an in vivo xenograft MCL mouse model. Results: CD83 is expressed on MCL, and its upregulation is correlated with the nuclear factor κB (NF-κB) activation. CD83 ADC kills MCL in vitro and in vivo. Doxorubicin and cyclophosphamide (CP), which are included in the current treatment regimen for MCL, enhance the NF-κB activity and increase CD83 expression on MCL cell lines. The combination of CD83 ADC with doxorubicin and CP has synergistic killing effect of MCL. Conclusion: This study provides evidence that a novel immunotherapeutic agent CD83 ADC, in combination with chemotherapy, has the potential to enhance the efficacy of current treatments for MCL

The effects of nitroxyl (HNO) on soluble guanylate cyclase activity: interactions at ferrous heme and cysteine thiols

It has been previously proposed that nitric oxide (NO) is the only biologically relevant nitrogen oxide capable of activating the enzyme soluble guanylate cyclase (sGC). However, recent reports implicate HNO as another possible activator of sGC. Herein, we examine the affect of HNO donors on the activity of purified bovine lung sGC and find that, indeed, HNO is capable of activating this enzyme. Like NO, HNO activation appears to occur via interaction with the regulatory ferrous heme on sGC. Somewhat unexpectedly, HNO does not activate the ferric form of the enzyme. Finally, HNO-mediated cysteine thiol modification appears to also affect enzyme activity leading to inhibition. Thus, sGC activity can be regulated by HNO via interactions at both the regulatory heme and cysteine thiols

Inverse relationship between oligoclonal expanded CD69- TTE and CD69+ TTE cells in bone marrow of multiple myeloma patients.

CD8+CD57+ terminal effector T (TTE) cells are a component of marrow-infiltrating lymphocytes and may contribute to the altered immune responses in multiple myeloma (MM) patients. We analyzed TTE cells in the bone marrow (BM) and peripheral blood (PB) of age-matched controls and patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering MM (SMM), and newly diagnosed (ND) MM using flow cytometry, mass cytometry, and FlowSOM clustering. TTE cells are heterogeneous in all subjects, with BM containing both CD69- and CD69+ subsets, while only CD69- cells are found in PB. Within the BM-TTE compartment, CD69- and CD69+ cells are found in comparable proportions in controls, while CD69- cells are dominant in MGUS and SMM and predominantly either CD69- or CD69+ cells in NDMM. A positive relationship between CD69+TTE and CD69-TTE cells is observed in the BM of controls, lost in MGUS, and converted to an inverse relationship in NDMM. CD69-TTE cells include multiple oligoclonal expansions of T-cell receptor/Vβ families shared between BM and PB of NDMM. Oligoclonal expanded CD69-TTE cells from the PB include myeloma-reactive cells capable of killing autologous CD38hi plasma cells in vitro, involving degranulation and high expression of perforin and granzyme. In contrast to CD69-TTE cells, oligoclonal expansions are not evident within CD69+TTE cells, which possess low perforin and granzyme expression and high inhibitory checkpoint expression and resemble T resident memory cells. Both CD69-TTE and CD69+TTE cells from the BM of NDMM produce large amounts of the inflammatory cytokines interferon-γ and tumor necrosis factor α. The balance between CD69- and CD69+ cells within the BM-TTE compartment may regulate immune responses in NDMM and contribute to the clinical heterogeneity of the disease

Impact Factor: outdated artefact or stepping-stone to journal certification?

A review of Garfield's journal impact factor and its specific implementation as the Thomson Reuters Impact Factor reveals several weaknesses in this commonly-used indicator of journal standing. Key limitations include the mismatch between citing and cited documents, the deceptive display of three decimals that belies the real precision, and the absence of confidence intervals. These are minor issues that are easily amended and should be corrected, but more substantive improvements are needed. There are indications that the scientific community seeks and needs better certification of journal procedures to improve the quality of published science. Comprehensive certification of editorial and review procedures could help ensure adequate procedures to detect duplicate and fraudulent submissions.Comment: 25 pages, 12 figures, 6 table

Fructose-1,6-Bisphosphatase Overexpression in Pancreatic β-Cells Results in Reduced Insulin Secretion : A New Mechanism for Fat-Induced Impairment of β-Cell Function

OBJECTIVE—Fructose-1,6-bisphosphatase (FBPase) is a gluconeogenic enzyme that is upregulated in islets or pancreatic β-cell lines exposed to high fat. However, whether specific β-cell upregulation of FBPase can impair insulin secretory function is not known. The objective of this study therefore is to determine whether a specific increase in islet β-cell FBPase can result in reduced glucose-mediated insulin secretion

2021 Update of the International Council for Standardization in Haematology Recommendations for Laboratory Measurement of Direct Oral Anticoagulants

International audienceIn 2018, the International Council for Standardization in Haematology (ICSH) published a consensus document providing guidance for laboratories on measuring direct oral anticoagulants (DOACs). Since that publication, several significant changes related to DOACs have occurred, including the approval of a new DOAC by the Food and Drug Administration, betrixaban, and a specific DOAC reversal agent intended for use when the reversal of anticoagulation with apixaban or rivaroxaban is needed due to life-threatening or uncontrolled bleeding, andexanet alfa. In addition, this ICSH Working Party recognized areas where additional information was warranted, including patient population considerations and updates in point-of-care testing. The information in this manuscript supplements our previous ICSH DOAC laboratory guidance document. The recommendations provided are based on (1) information from peer-reviewed publications about laboratory measurement of DOACs, (2) contributing author's personal experience/expert opinion and (3) good laboratory practice

Bacterial Transmembrane Proteins that Lack N-Terminal Signal Sequences

Tail-anchored membrane proteins (TAMPs), a class of proteins characterized by their lack of N-terminal signal sequence and Sec-independent membrane targeting, play critical roles in apoptosis, vesicle trafficking and other vital processes in eukaryotic organisms. Until recently, this class of membrane proteins has been unknown in bacteria. Here we present the results of bioinformatic analysis revealing proteins that are superficially similar to eukaryotic TAMPs in the bacterium Streptomyces coelicolor. We demonstrate that at least four of these proteins are bona fide membrane-spanning proteins capable of targeting to the membrane in the absence of their N-terminus and the C-terminal membrane-spanning domain is sufficient for membrane targeting. Several of these proteins, including a serine/threonine kinase and the SecE component of the Sec translocon, are widely conserved in bacteria