Publications by authors named "Marc Berger"

190 Publications

[Diagnosis and management of splenomegaly].

Rev Prat 2021 Feb;71(2):e71

"Service d'hématologie biologique, Équipe d'accueil 7453 Chelter, université Clermont-Auvergne, CHU Clermont-Ferrand, hôpital Estaing, 63003 Clermont-Ferrand Cedex 1, France".

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February 2021

[Splenomegaly Part : Adults].

Rev Prat 2021 Feb;71(2):e63-e70

"Service d'hématologie biologique, Équipe d'accueil 7453 Chelter, université Clermont-Auvergne, CHU Clermont-Ferrand, hôpital Estaing, 63003 Clermont-Ferrand Cedex 1, France".

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February 2021

No Detectable Alteration of Inorganic Allogeneic Bone Matrix Colonizing Mesenchymal Cells: A Step Towards Personalized Bone Grafts.

J Bone Metab 2021 May 31;28(2):161-169. Epub 2021 May 31.

Université Clermont Auvergne, CHU Clermont-Ferrand, GECOM, CRB Auvergne, Clermont-Ferrand, France.

Background: During major bone substance loss, secured allogeneic bone matrix (ABM) is normally utilized for bone repair. Here, we propose a method to colonize ABM using autologous mesenchymal cells (MCs) to improve their integration. Moreover, in this study, the consequences of in vitro colonization on MCs have been evaluated.

Methods: After in vitro propagation of MCs, their proliferation kinetics on ABM pre-coated with gelatin, fibronectin, collagen IV and human serum (HS) was monitored, and they were compared with cells cultured without ABM for 8 weeks. The effect of ABM on cell phenotype was also assessed. Lastly, the ability of ABM-colonizing MCs to perform hematopoiesis, a function normally preserved in selected culture conditions, and their differentiation towards osteoblastic lineage were evaluated.

Results: MC and colony-forming unit-fibroblast proliferated 930- and 590-fold, respectively. The proliferation rate of the expanded MCs was higher, forming a 3-dimensional structure in all ABMs. Pre-coating with HS was the most efficient treatment of ABMs to increase the initial adherence of MCs, and it partly explains the reason for the higher propagation of MCs. Flow cytometry analyses revealed subtle alterations in ABM-colonizing cells; however, the ability of MCs to maintain long-term culture initiating cells proliferation and differentiate into osteoblastic lineage was preserved.

Conclusions: In this study, the in vitro biocompatibility of bone marrow (BM) MCs with ABMs, the role of HS in scaffold coating, and the possibility of initially using a small BM sample for this approach were demonstrated.
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http://dx.doi.org/10.11005/jbm.2021.28.2.161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206612PMC
May 2021

Characteristics of Critically Ill Patients with COVID-19 Compared to Patients with Influenza-A Single Center Experience.

J Clin Med 2021 May 11;10(10). Epub 2021 May 11.

Department of Anesthesiology and Intensive Care Medicine, Faculty of Medicine and University Hospital Essen, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany.

Infections with SARS-CoV-2 spread worldwide early in 2020. In previous winters, we had been treating patients with seasonal influenza. While creating a larger impact on the health care systems, comparisons regarding the intensive care unit (ICU) courses of both diseases are lacking. We compared patients with influenza and SARS-CoV-2 infections treated at a tertiary care facility offering treatment for acute respiratory distress syndrome (ARDS) and being a high-volume facility for extracorporeal membrane oxygenation (ECMO). Patients with COVID-19 during the first wave of the pandemic ( = 64) were compared to 64 patients with severe influenza from 2016 to 2020 at our ICU. All patients were treated using a standardized protocol. ECMO was used in cases of severe ARDS. Both groups had similar comorbidities. Time in ICU and mortality were not significantly different, yet mortality with ECMO was high amongst COVID-19 patients with approximately two-thirds not surviving. This is in contrast to a mortality of less than 40% in influenza patients with ECMO. Mortality was higher than estimated by SAPSII score on admission in both groups. Patients with COVID-19 were more likely to be male and non-smokers than those with influenza. The outcomes for patients with severe disease were similar. The study helps to understand similarities and differences between patients treated for severe influenza infections and COVID-19.
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http://dx.doi.org/10.3390/jcm10102056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8150703PMC
May 2021

The Magnitude and Functionality of SARS-CoV-2 Reactive Cellular and Humoral Immunity in Transplant Population Is Similar to the General Population Despite Immunosuppression.

Transplantation 2021 Mar 18. Epub 2021 Mar 18.

1Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin-Brandenburg Center for Regenerative Therapies, and Institute of Medical Immunology, Germany 2Center for Translational Medicine and Immune Diagnostics Laboratory, Medical Department I, Marien Hospital Herne, University Hospital of the Ruhr-University Bochum, Germany 3Department of Infectious Diseases, West German Centre of Infectious Diseases, University Hospital Essen, University Duisburg-Essen, Germany 4Department of Anesthesiology, University Hospital Essen, University Duisburg-Essen, Germany 5Department of Immunology, Labor Berlin GmbH, Berlin, Germany 6Ruhr-University Bochum, University Hospital Knappschaftskrankenhaus Bochum, Department of Surgery, Bochum, Germany.

Background: The ability of transplant (Tx)-patients to generate a protective antiviral response under immunosuppression is pivotal in COVID-19 infection. However, analysis of immunity against SARS-COV-2 is currently lacking.

Methods: Here, we analyzed T cell immunity directed against SARS-CoV-2 spike-, membrane-, and nucleocapsid-protein by flow cytometry and spike-specific neutralizing antibodies in ten Tx in comparison to 26 nonimmunosuppressed (non-Tx) COVID-19 patients.

Results: Tx-patients (seven renal, one lung, and two combined pancreas-kidney transplants) were recruited in this study during the acute phase of COVID-19 with a median time after SARS-CoV-2-positivity of 3 and 4 days for non-Tx- and Tx-patients, respectively. Despite immunosuppression, we detected antiviral CD4 T cell-response in 90% of Tx-patients. SARS-CoV-2-reactive CD4 T cells produced multiple pro-inflammatory cytokines, indicating their potential protective capacity. Neutralizing antibody-titers did not differ between groups. SARS-CoV-2-reactive CD8+ T cells targeting membrane- and spike-protein were lower in Tx-patients, albeit without statistical significance. However, frequencies of anti-nucleocapsid-protein-reactive, and anti-SARS-CoV-2 polyfunctional CD8 T cells, were similar between patient cohorts. Tx-patients showed features of a prematurely aged adaptive immune system, but equal frequencies of SARS-CoV-2-reactive memory T cells.

Conclusions: In conclusion, a polyfunctional T cell immunity directed against SARS-CoV-2-proteins as well as neutralizing antibodies can be generated in Tx-patients despite immunosuppression. In comparison to nonimmunosuppressed-patients, no differences in humoral and cellular antiviral-immunity were found. Our data presenting the ability to generate SARS-CoV-2-specific immunity in immunosuppressed patients has implications for the handling of SARS-CoV-2-infected Tx patients and raises hopes for effective vaccination in this cohort.Supplemental Visual Abstract; http://links.lww.com/TP/C186.
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http://dx.doi.org/10.1097/TP.0000000000003755DOI Listing
March 2021

How Geometry Affects Sensitivity of a Differential Transformer for Contactless Characterization of Liquids.

Sensors (Basel) 2021 Mar 29;21(7). Epub 2021 Mar 29.

Department of Sensors and Measurement Technology, Institute of Electrical Engineering and Measurement Technology, Leibniz University Hannover, 30167 Hannover, Germany.

The electrical and dielectric properties of liquids can be used for sensing. Specific applications, e.g., the continuous in-line monitoring of blood conductivity as a measure of the sodium concentration during dialysis treatment, require contactless measuring methods to avoid any contamination of the medium. The differential transformer is one promising approach for such applications, since its principle is based on a contactless, magnetically induced conductivity measurement. The objective of this work is to investigate the impact of the geometric parameters of the sample or medium under test on the sensitivity and the noise of the differential transformer to derive design rules for an optimized setup. By fundamental investigations, an equation for the field penetration depth of a differential transformer is derived. Furthermore, it is found that increasing height and radius of the medium is accompanied by an enhancement in sensitivity and precision.
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http://dx.doi.org/10.3390/s21072365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038047PMC
March 2021

Efficiency of nilotinib to target chronic phase-chronic myeloid leukaemia primary mature CD34 and immature CD34 cells.

Sci Rep 2021 Mar 17;11(1):6187. Epub 2021 Mar 17.

Hématologie Biologique, CHU Clermont-Ferrand, Hôpital Estaing, 1 place Lucie et Raymond Aubrac, 63003, Clermont-Ferrand Cedex 1, France.

Accumulation in target cells is an essential pharmacokinetic step of targeted therapies. Tyrosine Kinase Inhibitors (TKI) against the BCR-ABL fusion protein in Chronic Phase-Chronic Myeloid Leukaemia (CP-CML) cells constitute a unique model in terms of efficacy, specificity, and in vivo demonstration of response heterogeneity by target cells. The overall therapeutic response to nilotinib is heterogeneous with no satisfactory explanation. To better understand the patients' response heterogeneity, we quantified nilotinib uptake by primary CP-CML cells in standardized conditions using flow cytometry, which allowed also distinguishing mature (polymorphonuclear cells) from immature (CD34) cells. Nilotinib was undetectable in 13.3% of PMN and 40% of CD34 cells. Moreover, in CD34 cells, intracellular nilotinib did not completely abolish BCR-ABL activity (monitored by CrkL phosphorylation inhibition), although nilotinib accumulated well in most CD34 cell samples. Intracellular nilotinib concentration was inversely correlated with disease burden parameters, Sokal score, and early haematologic response at day 6 ± 1 only in PMN, suggesting an intrinsic ability to limit nilotinib entry in the forms with higher tumor cell burdenat diagnosis. These findings suggest that nilotinib accumulation in CP-CML cells is influenced by individual characteristics and intra-clonal heterogeneity, and might be used for pharmacokinetic studies and to assess the therapeutic response.
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http://dx.doi.org/10.1038/s41598-021-85734-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969931PMC
March 2021

Interleukin-3 is a predictive marker for severity and outcome during SARS-CoV-2 infections.

Nat Commun 2021 02 18;12(1):1112. Epub 2021 Feb 18.

Department of Surgery, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a worldwide health threat. In a prospective multicentric study, we identify IL-3 as an independent prognostic marker for the outcome during SARS-CoV-2 infections. Specifically, low plasma IL-3 levels is associated with increased severity, viral load, and mortality during SARS-CoV-2 infections. Patients with severe COVID-19 exhibit also reduced circulating plasmacytoid dendritic cells (pDCs) and low plasma IFNα and IFNλ levels when compared to non-severe COVID-19 patients. In a mouse model of pulmonary HSV-1 infection, treatment with recombinant IL-3 reduces viral load and mortality. Mechanistically, IL-3 increases innate antiviral immunity by promoting the recruitment of circulating pDCs into the airways by stimulating CXCL12 secretion from pulmonary CD123 epithelial cells, both, in mice and in COVID-19 negative patients exhibiting pulmonary diseases. This study identifies IL-3 as a predictive disease marker for SARS-CoV-2 infections and as a potential therapeutic target for pulmunory viral infections.
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http://dx.doi.org/10.1038/s41467-021-21310-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893044PMC
February 2021

COVID-19 immune signatures reveal stable antiviral T cell function despite declining humoral responses.

Immunity 2021 02;54(2):340-354.e6

Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Hannover, Germany. Electronic address:

Cellular and humoral immunity to SARS-CoV-2 is critical to control primary infection and correlates with severity of disease. The role of SARS-CoV-2-specific T cell immunity, its relationship to antibodies, and pre-existing immunity against endemic coronaviruses (huCoV), which has been hypothesized to be protective, were investigated in 82 healthy donors (HDs), 204 recovered (RCs), and 92 active COVID-19 patients (ACs). ACs had high amounts of anti-SARS-CoV-2 nucleocapsid and spike IgG but lymphopenia and overall reduced antiviral T cell responses due to the inflammatory milieu, expression of inhibitory molecules (PD-1, Tim-3) as well as effector caspase-3, -7, and -8 activity in T cells. SARS-CoV-2-specific T cell immunity conferred by polyfunctional, mainly interferon-γ-secreting CD4 T cells remained stable throughout convalescence, whereas humoral responses declined. Immune responses toward huCoV in RCs with mild disease and strong cellular SARS-CoV-2 T cell reactivity imply a protective role of pre-existing immunity against huCoV.
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http://dx.doi.org/10.1016/j.immuni.2021.01.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871825PMC
February 2021

Long-term outcome of imatinib 400 mg compared to imatinib 600 mg or imatinib 400 mg daily in combination with cytarabine or pegylated interferon alpha 2a for chronic myeloid leukaemia: results from the French SPIRIT phase III randomised trial.

Leukemia 2021 Jan 22. Epub 2021 Jan 22.

Inserm CIC 1427, Université de Paris, Paris, France.

The STI571 prospective randomised trial (SPIRIT) French trial is a four-arm study comparing imatinib (IM) 400 mg versus IM 600 mg, IM 400 mg + cytarabine (AraC), and IM 400 mg + pegylated interferon alpha2a (PegIFN-α2a) for the front-line treatment of chronic-phase chronic myeloid leukaemia (CML). Long-term analyses included overall and progression-free survival, molecular responses to treatment, and severe adverse events. Starting in 2003, the trial included 787 evaluable patients. The median overall follow-up of the patients was 13.5 years (range 3 months to 16.7 years). Based on intention-to-treat analyses, at 15 years, overall and progression-free survival were similar across arms: 85%, 83%, 80%, and 82% and 84%, 87%, 79%, and 79% for the IM 400 mg (N = 223), IM 600 mg (N = 171), IM 400 mg + AraC (N = 172), and IM 400 mg + PegIFN-α2a (N = 221) arms, respectively. The rate of major molecular response at 12 months and deep molecular response (MR4) over time were significantly higher with the combination IM 400 mg + PegIFN-α2a than with IM 400 mg: p = 0.0001 and p = 0.0035, respectively. Progression to advanced phases and secondary malignancies were the most frequent causes of death. Toxicity was the main reason for stopping AraC or PegIFN-α2a treatment.
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http://dx.doi.org/10.1038/s41375-020-01117-wDOI Listing
January 2021

Double L611S/V617F JAK2 mutation in a child with erythrocytosis.

Pediatr Blood Cancer 2021 Apr 12;68(4):e28816. Epub 2020 Dec 12.

Hématologie (Biologie), Centre Hospitalier Universitaire de Clermont-Ferrand, CHU Estaing, Clermont-Ferrand, France.

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http://dx.doi.org/10.1002/pbc.28816DOI Listing
April 2021

COVID-19-Induced ARDS Is Associated with Decreased Frequency of Activated Memory/Effector T Cells Expressing CD11a.

Mol Ther 2020 12 8;28(12):2691-2702. Epub 2020 Oct 8.

Center for Translational Medicine and Immune Diagnostics Laboratory, Medical Department I, Marien Hospital Herne, University Hospital of the Ruhr University Bochum, Hölkeskampring 40, 44625 Herne, Germany.

Preventing the progression to acute respiratory distress syndrome (ARDS) in COVID-19 is an unsolved challenge. The involvement of T cell immunity in this exacerbation remains unclear. To identify predictive markers of COVID-19 progress and outcome, we analyzed peripheral blood of 10 COVID-19-associated ARDS patients and 35 mild/moderate COVID-19 patients, not requiring intensive care. Using multi-parametric flow cytometry, we compared quantitative, phenotypic, and functional characteristics of circulating bulk immune cells, as well as SARS-CoV-2 S-protein-reactive T cells between the two groups. ARDS patients demonstrated significantly higher S-protein-reactive CD4 and CD8 T cells compared to non-ARDS patients. Of interest, comparison of circulating bulk T cells in ARDS patients to non-ARDS patients demonstrated decreased frequencies of CD4 and CD8 T cell subsets, with activated memory/effector T cells expressing tissue migration molecule CD11a. Importantly, survival from ARDS (4/10) was accompanied by a recovery of the CD11a T cell subsets in peripheral blood. Conclusively, data on S-protein-reactive polyfunctional T cells indicate the ability of ARDS patients to generate antiviral protection. Furthermore, decreased frequencies of activated memory/effector T cells expressing tissue migratory molecule CD11a observed in circulation of ARDS patients might suggest their involvement in ARDS development and propose the CD11a-based immune signature as a possible prognostic marker.
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http://dx.doi.org/10.1016/j.ymthe.2020.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543694PMC
December 2020

Serum neurofilament level increases after ascent to 4559 m but is not related to acute mountain sickness.

Eur J Neurol 2021 Mar 26;28(3):1004-1008. Epub 2020 Nov 26.

Department of Neurology, Medical University of Graz, Graz, Austria.

Background And Purpose: At high altitude the brain is exposed to hypoxic stress, which may result in neurological conditions, with acute mountain sickness (AMS) being the most common. We aimed to test the hypothesis that rapid ascent to high altitude alters neuro-axonal integrity, which can be detected by increased concentration of serum neurofilament light (sNfL) in the blood and may even be exaggerated in people with AMS.

Methods: Serum neurofilament light was measured using a single-molecule array (Simoa, Quanterix, Lexington, MA, USA) assay at low altitude (423 m) in 47 healthy study participants and 44 h after rapid and active ascent to high altitude (4559 m). Peripheral oxygen saturation (SpO ) and partial pressures of oxygen (pO ) were obtained at low and high altitude. The Acute Mountain Sickness-Cerebral (AMS-C) scoring system was used to assess AMS incidence and AMS severity.

Results: There was an increase in sNfL from its baseline value compared with its value at high altitude (6.34 ± 1.96 vs. 7.19 ± 3.14 pg/ml; p = 0.014), but sNfL level did not correlate with SpO (r = -0.19; p = 0.066) or pO (r = -0.19; p = 0.068). The incidence of AMS at high altitude was 62%. Neither at low altitude (p = 0.706) nor at high altitude (p = 0.985) was there a difference in sNfL between participants with and without AMS as measured 3 days after rapid ascent and 44 h of high-altitude exposure. Altitude sNfL did not correlate with AMS-C, either overall or with single-item scores such as headache severity.

Conclusions: Rapid ascent of healthy people to high altitude provokes an increase in sNfL 44 h after arrival at 4559 m, which is not related to the magnitude of hypoxemia or AMS incidence and severity, suggesting that neuro-axonal injury does not directly contribute to AMS.
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http://dx.doi.org/10.1111/ene.14606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898504PMC
March 2021

No Relevant Analogy Between COVID-19 and Acute Mountain Sickness.

High Alt Med Biol 2020 12 22;21(4):315-318. Epub 2020 Sep 22.

Department of Internal Medicine, University of Heidelberg, Heidelberg, Germany.

Berger, Marc Moritz, Peter H. Hackett, and Peter Bärtsch. No relevant analogy between COVID-19 and acute mountain sickness. . 21:315-318, 2020.-Clinicians and scientists have suggested therapies for coronavirus disease-19 (COVID-19) that are known to be effective for other medical conditions. A recent publication suggests that pathophysiological mechanisms underlying acute mountain sickness (a syndrome of nonspecific neurological symptoms typically experienced by nonacclimatized individuals at altitudes >2500 m) may overlap with the mechanisms causing COVID-19. In this short review, we briefly evaluate this mistaken analogy and demonstrate that this concept is not supported by scientific evidence.
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http://dx.doi.org/10.1089/ham.2020.0147DOI Listing
December 2020

Impaired Cytotoxic CD8 T Cell Response in Elderly COVID-19 Patients.

mBio 2020 09 18;11(5). Epub 2020 Sep 18.

Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection induces a T cell response that most likely contributes to virus control in COVID-19 patients but may also induce immunopathology. Until now, the cytotoxic T cell response has not been very well characterized in COVID-19 patients. Here, we analyzed the differentiation and cytotoxic profile of T cells in 30 cases of mild COVID-19 during acute infection. SARS-CoV-2 infection induced a cytotoxic response of CD8 T cells, but not CD4 T cells, characterized by the simultaneous production of granzyme A and B as well as perforin within different effector CD8 T cell subsets. PD-1-expressing CD8 T cells also produced cytotoxic molecules during acute infection, indicating that they were not functionally exhausted. However, in COVID-19 patients over the age of 80 years, the cytotoxic T cell potential was diminished, especially in effector memory and terminally differentiated effector CD8 cells, showing that elderly patients have impaired cellular immunity against SARS-CoV-2. Our data provide valuable information about T cell responses in COVID-19 patients that may also have important implications for vaccine development. Cytotoxic T cells are responsible for the elimination of infected cells and are key players in the control of viruses. CD8 T cells with an effector phenotype express cytotoxic molecules and are able to perform target cell killing. COVID-19 patients with a mild disease course were analyzed for the differentiation status and cytotoxic profile of CD8 T cells. SARS-CoV-2 infection induced a vigorous cytotoxic CD8 T cell response. However, this cytotoxic profile of T cells was not detected in COVID-19 patients over the age of 80 years. Thus, the absence of a cytotoxic response in elderly patients might be a possible reason for the more frequent severity of COVID-19 in this age group than in younger patients.
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http://dx.doi.org/10.1128/mBio.02243-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502863PMC
September 2020

Improving Transparency to Build Trust in Real-World Secondary Data Studies for Hypothesis Testing-Why, What, and How: Recommendations and a Road Map from the Real-World Evidence Transparency Initiative.

Value Health 2020 09;23(9):1128-1136

ISPOR, Lawrenceville, NJ, USA.

Real-world data (RWD) and the derivations of these data into real-world evidence (RWE) are rapidly expanding from informing healthcare decisions at the patient and health system level to influencing major health policy decisions, including regulatory approvals and coverage. Recent examples include the approval of palbociclib in combination with endocrine therapy for male breast cancer and the inclusion of RWE in the label of paliperidone palmitate for schizophrenia. This interest has created an urgency to develop processes that promote trust in the evidence-generation process. Key stakeholders and decision-makers include patients and their healthcare providers; learning health systems; health technology assessment bodies and payers; pharmacoepidemiologists and other clinical reseachers, and policy makers interested in bioethical and regulatory issues. A key to optimal uptake of RWE is transparency of the research process to enable decision-makers to evaluate the quality of the methods used and the applicability of the evidence that results from the RWE studies. Registration of RWE studies-particularly for hypothesis evaluating treatment effectiveness (HETE) studies-has been proposed to improve transparency, trust, and research replicability. Although registration would not guarantee better RWE studies would be conducted, it would encourage the prospective disclosure of study plans, timing, and rationale for modifications. A joint task force of the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) and the International Society for Pharmacoepidemiology (ISPE) recommended that investigators preregister their RWE studies and post their study protocols in a publicly available forum before starting studies to reduce publication bias and improve the transparency of research methods. Recognizing that published recommendations alone are insufficient, especially without accessible registration options and with no incentives, a group of experts gathered on February 25 and 26, 2019, in National Harbor, Maryland, to explore the structural and practical challenges to the successful implementation of the recommendations of the ISPOR/ISPE task force for preregistration. This positioning article describes a plan for making registration of HETE RWE studies routine. The plan includes specifying the rationale for registering HETE RWE studies, the studies that should be registered, where and when these studies should be registered, how and when analytic deviations from protocols should be reported, how and when to publish results, and incentives to encourage registration. Table 1 summarizes the rationale, goals, and potential solutions that increase transparency, in addition to unique concerns about secondary data studies. Definitions of terms used throughout this report are provided in Table 2.
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http://dx.doi.org/10.1016/j.jval.2020.04.002DOI Listing
September 2020

Improving transparency to build trust in real-world secondary data studies for hypothesis testing-Why, what, and how: recommendations and a road map from the real-world evidence transparency initiative.

Pharmacoepidemiol Drug Saf 2020 11 13;29(11):1504-1513. Epub 2020 Sep 13.

ISPOR, Lawrenceville, New Jersey, USA.

Real-world data (RWD) and the derivations of these data into real-world evidence (RWE) are rapidly expanding from informing healthcare decisions at the patient and health system level to influencing major health policy decisions, including regulatory approvals and coverage. Recent examples include the approval of palbociclib in combination with endocrine therapy for male breast cancer and the inclusion of RWE in the label of paliperidone palmitate for schizophrenia. This interest has created an urgency to develop processes that promote trust in the evidence-generation process. Key stakeholders and decision-makers include patients and their healthcare providers; learning health systems; health technology assessment bodies and payers; pharmacoepidemiologists and other clinical reseachers, and policy makers interested in bioethical and regulatory issues. A key to optimal uptake of RWE is transparency of the research process to enable decision-makers to evaluate the quality of the methods used and the applicability of the evidence that results from the RWE studies. Registration of RWE studies-particularly for hypothesis evaluating treatment effectiveness (HETE) studies-has been proposed to improve transparency, trust, and research replicability. Although registration would not guarantee better RWE studies would be conducted, it would encourage the prospective disclosure of study plans, timing, and rationale for modifications. A joint task force of the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) and the International Society for Pharmacoepidemiology (ISPE) recommended that investigators preregister their RWE studies and post their study protocols in a publicly available forum before starting studies to reduce publication bias and improve the transparency of research methods. Recognizing that published recommendations alone are insufficient, especially without accessible registration options and with no incentives, a group of experts gathered on February 25 and 26, 2019, in National Harbor, Maryland, to explore the structural and practical challenges to the successful implementation of the recommendations of the ISPOR/ISPE task force for preregistration. This positioning article describes a plan for making registration of HETE RWE studies routine. The plan includes specifying the rationale for registering HETE RWE studies, the studies that should be registered, where and when these studies should be registered, how and when analytic deviations from protocols should be reported, how and when to publish results, and incentives to encourage registration. Table 1 summarizes the rationale, goals, and potential solutions that increase transparency, in addition to unique concerns about secondary data studies. Definitions of terms used throughout this report are provided in Table 2.
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http://dx.doi.org/10.1002/pds.5079DOI Listing
November 2020

Robust T Cell Response Toward Spike, Membrane, and Nucleocapsid SARS-CoV-2 Proteins Is Not Associated with Recovery in Critical COVID-19 Patients.

Cell Rep Med 2020 Sep 29;1(6):100092. Epub 2020 Aug 29.

Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, BIH Center for Regenerative Therapies, Berlin, Berlin, Germany.

T cell immunity toward SARS-CoV-2 spike (S-), membrane (M-), and nucleocapsid (N-) proteins may define COVID-19 severity. Therefore, we compare the SARS-CoV-2-reactive T cell responses in moderate, severe, and critical COVID-19 patients and unexposed donors. Overlapping peptide pools of all three proteins induce SARS-CoV-2-reactive T cell response with dominance of CD4 over CD8 T cells and demonstrate interindividual immunity against the three proteins. M-protein induces the highest frequencies of CD4 T cells, suggesting its relevance for diagnosis and vaccination. The T cell response of critical COVID-19 patients is robust and comparable or even superior to non-critical patients. Virus clearance and COVID-19 survival are not associated with either SARS-CoV-2 T cell kinetics or magnitude of T cell responses, respectively. Thus, our data do not support the hypothesis of insufficient SARS-CoV-2-reactive immunity in critical COVID-19. Conversely, it indicates that activation of differentiated memory effector T cells could cause hyperreactivity and immunopathogenesis in critical patients.
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http://dx.doi.org/10.1016/j.xcrm.2020.100092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456276PMC
September 2020

A Cross-Sectional Retrospective Study of Non-Splenectomized and Never-Treated Patients with Type 1 Gaucher Disease.

J Clin Med 2020 Jul 22;9(8). Epub 2020 Jul 22.

University Hospital of Clermont Ferrand, Hematology Biology Department, 63000 Clermont-Ferrand, France.

Patients with type 1 Gaucher disease (GD1) present thrombocytopenia, anemia, organomegaly, and bone complications. Most experts consider that the less aggressive forms do not require specific treatment. However, little is known about the disease course of these forms. The objective of this cross-sectional retrospective study was to compare the clinical, radiological, and laboratory characteristics of patients with less severe GD1 at diagnosis and at the last evaluation to identify features that might lead to potential complications. Non-splenectomized and never-treated patients (19 women and 17 men) were identified in the French Gaucher Disease Registry (FGDR). Their median age was 36.6 years (2.4-75.1), and their median follow-up was 7.8 years (0.4-32.4). Moreover, 38.7% were heterozygous for the N370S variant, and 22.6% for the L444P variant. From diagnosis to the last evaluation, GD1 did not worsen in 75% of these patients. Some parameters improved (fatigue and hemoglobin concentration), whereas platelet count and chitotriosidase level remained stable. In one patient (2.7%), Lewy body dementia was diagnosed at 46 years of age. Bone lesion onset was late and usually a single event in most patients. This analysis highlights the genotypic heterogeneity of this subgroup, in which disease could remain stable and even improve spontaneously. It also draws attention to the possible risk of Lewy body disease and late onset of bone complications, even if isolated, to be confirmed in larger series and with longer follow-up.
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http://dx.doi.org/10.3390/jcm9082343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464688PMC
July 2020

MNDA controls the expression of MCL-1 and BCL-2 in chronic lymphocytic leukemia cells.

Exp Hematol 2020 08 16;88:68-82.e5. Epub 2020 Jul 16.

Maisonneuve-Rosemont Hospital Research Center, University of Montreal, CIUSSS de l'Est-de-l'Île de Montréal, Montreal, QC, Canada; Department of Medicine, University of Montréal, Montréal, QC, Canada. Electronic address:

The myeloid nuclear differentiation antigen (MNDA) is a stress-induced protein that promotes degradation of the anti-apoptotic factor MCL-1 and apoptosis in myeloid cells. MNDA is also expressed in normal lymphoid cells and in B-cell clones isolated from individuals with chronic lymphocytic leukemia (CLL), a disease characterized by abnormal apoptosis control. We found that MNDA expression levels inversely correlate with the amount of the anti-apoptotic proteins MCL-1 and BCL-2 in human CLL samples. We report that in response to chemotherapeutic agents that induce genotoxic stress, MNDA exits its typical nucleolar localization and accumulates in the nucleoplasm of CLL and lymphoid cells. Then, MNDA binds chromatin at Mcl1 and Bcl2 genes and affects the transcriptional competence of RNA polymerase II. Our data also reveal that MNDA specifically associates with Mcl1 and Bcl2 (pre-) mRNAs and favors their rapid turnover as a prompt response to genotoxic stress. We propose that this rapid dynamic tuning of RNA levels, which leads to the destabilization of Mcl1 and Bcl2 transcripts, represents a post-transcriptional mechanism of apoptosis control in CLL cells. These results provide an explanation of previous clinical data and corroborate the finding that higher MNDA expression levels in CLL are associated with a better clinical course.
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http://dx.doi.org/10.1016/j.exphem.2020.07.004DOI Listing
August 2020

Influence of major transcript subtype on outcome in patients with chronic myeloid leukemia in chronic phase treated frontline with nilotinib.

Oncotarget 2020 Jun 30;11(26):2560-2570. Epub 2020 Jun 30.

French Group of CML, Bordeaux, France.

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the presence of transcript as a result of reciprocal translocation between chromosome 9 and 22. The most common transcripts subtypes are e13a2 (b2a2) and e14a2 (b3a2). The prognostic impact of the type of transcript has been the subject of controversies over time. In the imatinib era, several studies have suggested a deeper and faster response in patients expressing e14a2. However, the impact on response after first line therapy with a second-generation tyrosine kinase inhibitor, nilotinib, is unknown. We retrospectively evaluated 118 patients newly diagnosed with chronic phase CML and treated frontline with nilotinib inside or outside clinical trial in five French centers. Only patients expressing e14a2 or e13a2 transcripts alone were analyzed. At baseline, 55.3% expressed e14a2, 44.7% expressed e13a2. The median age was 51 years and median follow-up was 49 months. Relative risks of CML at diagnosis were similar according to the ELTS score ( = .87). Complete hematological response and complete cytogenetic response rates were similar among groups. Patients expressing e14a2 transcripts compared to e13a2 transcripts had deeper and faster molecular responses, when considering MMR (100% vs 84.1%, = .007) with a median time of 6.7 and 17.1 months or MR (100% vs 59.9%, = .005) with a median time of 39.7 and 70.9 months, respectively. A sustained treatment free remission was observed in 10/10 patients with e14a2 versus 1/3 with e13a2 transcript ( = .04). In conclusion, even treated with nilotinib first line, patients with chronic phase CML expressing e13a2 transcript have a lower rate of deep molecular responses.
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http://dx.doi.org/10.18632/oncotarget.27652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335668PMC
June 2020

Re: "Are Pre-Ascent Low-Altitude Saliva Cortisol Levels Related to the Subsequent Acute Mountain Sickness Score? Observations From a Field Study" by Gatterer et al.

High Alt Med Biol 2020 09 7;21(3):308-309. Epub 2020 May 7.

Department of Internal Medicine, University of Heidelberg, Heidelberg, Germany.

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http://dx.doi.org/10.1089/ham.2020.0050DOI Listing
September 2020

A Proteomics-Based Analysis Reveals Predictive Biological Patterns in Fabry Disease.

J Clin Med 2020 May 2;9(5). Epub 2020 May 2.

Department of Metabolic Biochemistry, Rouen University Hospital, 76000 Rouen, France.

: Fabry disease (FD) is an X-linked progressive lysosomal disease (LD) due to glycosphingolipid metabolism impairment. Currently, plasmatic globotriaosylsphingosine (LysoGb3) is used for disease diagnosis and monitoring. However, this biomarker is inconstantly increased in mild forms and in some female patients. : We applied a targeted proteomic approach to explore disease-related biological patterns that might explain the disease pathophysiology. Forty proteins, involved mainly in inflammatory and angiogenesis processes, were assessed in 69 plasma samples retrieved from the French Fabry cohort (FFABRY) and from 83 healthy subjects. For predictive performance assessment, we also included other LD samples (Gaucher, Pompe and Niemann Pick C). : The study yielded four discriminant proteins that include three angiogenesis proteins (fibroblast growth factor 2 (FGF2), vascular endothelial growth factor A (VEGFA), vascular endothelial growth factor C (VEGFC)) and one cytokine interleukin 7 (IL-7). A clear elevation of FGF2 and IL-7 concentrations was observed in FD compared to other LD samples. No correlation was observed between these proteins and globotriaosylsphingosine (LysoGb3). A significant correlation exists between IL-7 and residual enzyme activity in a non-classical phenotype. This highlights the orthogonal biological information yielded by these proteins that might help in stratifying Fabry patients. : This work highlights the potential of using proteomics approaches in exploring FD and enhancing FD diagnosis and therapeutic monitoring performances.
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http://dx.doi.org/10.3390/jcm9051325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290805PMC
May 2020

Measurements of eftrenonacog alfa by 19 different combinations reagents/instrument: A single-centre study.

Haemophilia 2020 May 20;26(3):543-552. Epub 2020 Apr 20.

Service d'Hématologie Biologique, CHU Clermont-Ferrand, Clermont-Ferrand, France.

Introduction: Recombinant factor IX Fc fusion protein (rFIXFc) is an extended half-life concentrate for the treatment of haemophilia B (HB). rFIXFc activity monitoring is crucial in several clinical situations. However, differences were observed between one-stage clotting (OSC) and chromogenic assays, but not for all factor IX (FIX) concentrations.

Aims: To compare rFIXFc measurements obtained using different instruments and common OSC and chromogenic asssays.

Methods: FIX:C measurements were performed in rFIXFc-spiked plasma aliquots (targeted FIX levels of 1.5, 1, 0.5, 0.2, 0.05, 0.02 and 0.01 IU/mL) and plasma samples collected from two patients with HB at various time points after rFIXFc infusion, using three instruments (STA-R MAX, ACLTOP700 and CS2100i) and common clotting and chromogenic FIX:C assays.

Results: The same reagent could give different FIX:C measurements when adapted to different instruments. Moreover, the same reagent/instrument combination could give different results depending of the FIX concentration. For OSC assays, only STA-Cephascreen on STA-R MAX and CS2100i, SynthAFax on ACLTOP 700 and Actin on CS2100i provided acceptable recoveries for all rFIXFc concentrations. The chromogenic assays ROX-FIX and Biophen FIX:C underestimated rFIXFc for concentrations lower than 0.05 and 0.2 IU/mL, respectively.

Conclusions: Our study demonstrates that the same reagent adapted to different instruments could lead to different rFIXFc values. As rFIXFc under/overestimation could be associated with inappropriate treatment or biased calculation of pharmacokinetic parameters, the reagent/instrument combination used by haemostasis laboratories should be considered and regularly evaluated by external quality assessment programmes.
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http://dx.doi.org/10.1111/hae.14003DOI Listing
May 2020

Rapid Ascent to 4559 m Is Associated with Increased Plasma Components of the Vascular Endothelial Glycocalyx and May Be Associated with Acute Mountain Sickness.

High Alt Med Biol 2020 06 17;21(2):176-183. Epub 2020 Mar 17.

Pulmonary, Critical Care and Sleep Medicine, VA Puget Sound Health Care System, University of Washington, Seattle, Washington, USA.

The stress of high altitude alters vascular permeability, which may be related to structural changes in the endothelial glycocalyx. We aimed to study these changes by measuring plasma concentrations of several glycocalyx components upon exposure to high altitude. Plasma collected from 17 subjects at low altitude (423 m) and at three time points (7, 20, and 44 hours) after rapid ascent to high altitude (4559 m) were evaluated for concentrations of three glycocalyx components: syndecan-1, intercellular adhesion molecule-1 (ICAM-1), and heparan sulfate. Vital signs and echocardiographic measurement of systolic pulmonary artery pressure (sPAP) and cardiac output were also obtained at low and high altitudes. Mean age of the study population was 35.5 ± 11.2 years with a body mass index of 22.7 ± 2.5 kg/m. Concentrations of ICAM-1 and heparan sulfate increased from baseline to 7 hours after arrival at high altitude; the ICAM-1 rise persisted at 20 hours. Syndecan-1 concentrations were increased only at 44 hours. Increased ICAM-1 concentrations correlated with sPAP and peripheral edema. Elevations in heparan sulfate appeared to correlate with acute mountain sickness (AMS). Levels of circulating glycocalyx components increase after exposure to high altitude and may correlate with AMS. Measuring plasma concentrations of various glycocalyx components could serve as a useful tool for further evaluation of vascular endothelial injury and repair in illness at high altitude.
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http://dx.doi.org/10.1089/ham.2019.0081DOI Listing
June 2020

Preserved right ventricular function but increased right atrial contractile demand in altitude-induced pulmonary hypertension.

Int J Cardiovasc Imaging 2020 Jun 9;36(6):1069-1076. Epub 2020 Mar 9.

University Institute of Sports Medicine, Prevention and Rehabilitation and Research Institute of Molecular Sports Medicine and Rehabilitation, Paracelsus Medical University, Lindhofstraße 20, 5020, Salzburg, Austria.

Purpose: Ascent to high altitude increases right ventricular (RV) afterload and decreases myocardial energy supply. This study evaluates physiologic variables and comprehensive echocardiographic indices of RV and right atrial (RA) function following rapid ascent to high altitude.

Methods: Fifty healthy volunteers actively ascended from 1130 to 4559 m in < 22 h. All participants underwent 2D echocardiography during baseline examination at low altitude (424 m) and at three study time-points (7, 20 and 44 h) after arrival at high altitude. In addition to systolic pulmonary artery pressure (sPAP), comprehensive 2D planimetric-, tissue Doppler- and speckle-tracking-derived strain indices of RA and RV function were obtained.

Results: sPAP increased from baseline (24 ± 4 mmHg) to the first altitude examination (39 ± 8 mmHg, p < 0.001) and remained elevated during the following 44 h. Global RV function did not change. RA reservoir strain showed a trend towards increase from baseline (50.2 ± 12.1%) to the first altitude examination (53.8 ± 11.0%, p = 0.07) secondary to a significant increase of RA contraction strain (19.2 ± 6.4 vs. 25.4 ± 9.6%, p < 0.001). Volumetric RA data largely paralleled RA strain results and RA active emptying volume was increased throughout the 44 h stay at high altitude.

Conclusion: Active and rapid ascent of healthy individuals to 4559 m is associated with an increased contractile performance of the RA that compensates for the increased workload of the RV.
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http://dx.doi.org/10.1007/s10554-020-01803-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7228961PMC
June 2020

Immunoglobulin Abnormalities in Gaucher Disease: an Analysis of 278 Patients Included in the French Gaucher Disease Registry.

Int J Mol Sci 2020 Feb 13;21(4). Epub 2020 Feb 13.

Service de Médecine Interne, Centre de Référence des Maladies Lysosomales, AP-HP.Nord, Site Beaujon, Université de Paris, F-92110 Clichy, France.

Gaucher disease (GD) is a rare lysosomal autosomal-recessive disorder due to deficiency of glucocerebrosidase; polyclonal gammopathy (PG) and/or monoclonal gammopathy (MG) can occur in this disease. We aimed to describe these immunoglobulin abnormalities in a large cohort of GD patients and to study the risk factors, clinical significance, and evolution. Data for patients enrolled in the French GD Registry were studied retrospectively. The risk factors of PG and/or MG developing and their association with clinical bone events and severe thrombocytopenia, two markers of GD severity, were assessed with multivariable Cox models and the effect of GD treatment on gammaglobulin levels with linear/logarithmic mixed models. Regression of MG and the occurrence of hematological malignancies were described. The 278 patients included (132 males, 47.5%) were followed up during a mean (SD) of 19 (14) years after GD diagnosis. PG occurred in 112/235 (47.7%) patients at GD diagnosis or during follow-up and MG in 59/187 (31.6%). Multivariable analysis retained age at GD diagnosis as the only independent risk factor for MG (> 30 vs. ≤30 years, HR 4.71, 95%CI [2.40-9.27]; < 0.001). Risk of bone events or severe thrombocytopenia was not significantly associated with PG or MG. During follow-up, non-Hodgkin lymphoma developed in five patients and multiple myeloma in one. MG was observed in almost one third of patients with GD. Immunoglobulin abnormalities were not associated with the disease severity. However, prolonged surveillance of patients with GD is needed because hematologic malignancies may occur.
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http://dx.doi.org/10.3390/ijms21041247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072938PMC
February 2020

Accuracy of chitotriosidase activity and CCL18 concentration in assessing type I Gaucher disease severity. A systematic review with meta-analysis of individual participant data.

Haematologica 2021 02 1;106(2):437-445. Epub 2021 Feb 1.

CHU Clermont-Ferrand, Hopital Estaing, Hematologie Biologique, Clermont-Ferrand, France.

Chitotriosidase activity and CCL18 concentration are interchangeably used for monitoring Gaucher disease (GD) activity, together with clinical assessment. However, comparative studies of these two biomarkers are scarce and of limited sample size. The aim of this systematic review with meta-analysis of individual participant data (IPD) was to compare the accuracy of chitotriosidase activity and CCL18 concentration for assessing type I GD severity. We identified cross-sectional and prospective cohort studies by searching Medline, EMBASE, and CENTRAL from 1995 to June 2017, and by contacting research groups. The primary outcome was a composite of liver volume >1.25 multiple of normal (MN), spleen volume >5 MN, hemoglobin concentration <11 g/dL, and platelet count <100x109/L. Overall, IPD included 1109 observations from 334 patients enrolled in nine primary studies, after excluding 111 patients with undocumented values and 18 patients with deficient chitotriosidase activity. IPD were unavailable for 14 eligible primary studies. The primary outcome was associated with a 5.3-fold (95% confidence interval [CI], 4.2 to 6.6) and 3.0-fold (95% CI, 2.6 to 3.6) increase of the geometric mean for chitotriosidase activity and CCL18 concentration, respectively. The corresponding areas under the receiver operating characteristics curves were 0.82 and 0.84 (summary difference, 0.02, 95% CI, -0.02 to 0.05). The addition of chitotriosidase activity did not improve the accuracy of CCL18 concentration. Estimates remained robust in the sensitivity analysis and consistent across subgroups. Neither chitotriosidase activity nor CCL18 concentration varied significantly according to a recent history of bone events among 97 patients. In conclusion, CCL18 concentration is as accurate as chitotriosidase activity in assessing hematological and visceral parameters of GD severity and can be measured in all GD patients. This meta-analysis supports the use of CCL18 rather than chitotriosidase activity for monitoring GD activity in routine practice.
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http://dx.doi.org/10.3324/haematol.2019.236083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849573PMC
February 2021

Semaphorin 7A: A novel marker of disease activity in Gaucher disease.

Am J Hematol 2020 05 7;95(5):483-491. Epub 2020 Feb 7.

Université de Paris, UMR_S1134, BIGR, Inserm, Institut National de Transfusion Sanguine, Laboratoire d'Excellence GR-Ex, Paris, France.

Gaucher disease (GD) is a recessively inherited lysosomal storage disorder in which sphingolipids accumulates in the macrophages that transform into Gaucher cells. A growing body of evidence indicates that red blood cells (RBCs) represent important actors in GD pathophysiology. We previously demonstrated that altered RBC properties including increased Lyso-GL1 levels, dyserythropoiesis, and iron metabolism defect in GD patients contribute to anemia and hyperferritinemia. Since RBC defects also correlated well with markers of GD severity and were normalized under enzyme replacement therapy (ERT), the identification of molecules that are deregulated in GD RBCs represents an important issue in the search of pertinent markers of the disease. Here, we found a decreased expression of the GPI-anchored cell surface protein Semaphorin 7A (Sema7A) in RBCs from untreated GD (GD UT) patients, in parallel with increased levels of the soluble form in the plasma. Sema7A plays a role in neural guidance, atherosclerosis, and inflammatory diseases and represents a promigratory cue in physiological and pathological conditions. We showed that the decreased expression of Sema7A in RBCs correlated with their abnormal properties and with markers of GD activity. Interestingly, ERT restored the level of Sema7A to normal values both in RBCs and in plasma from GD patients. We then proposed that SemaA7A represents a simple and pertinent marker of inflammation in GD. Finally, because Sema7A is known to regulate the activity of immune cells, the increased level of soluble Sema7A in GD patients could propagate inflammation in several tissues.
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http://dx.doi.org/10.1002/ajh.25744DOI Listing
May 2020