Publications by authors named "Michael Dussiot"

Although refrigerated storage slows the metabolism of volunteer donor RBCs, cellular aging still occurs throughout this process, which is essential in transfusion medicine. Storage-induced microerythrocytes (SMEs) are morphologically-altered senescent RBCs that accumulate during storage and which are cleared from circulation following transfusion. However, the molecular and cellular alterations that trigger clearance of this RBC subset remain to be identified.

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In children with sickle cell disease (SCD), splenectomy is immediately beneficial for acute sequestration crises and hypersplenism (ASSC/HyS) but portends a long-term risk of asplenia-related complications. We retrieved peripheral and splenic red blood cells (RBCs) from 17 SCD children/teenagers undergoing partial splenectomy for ASSC/HyS, 12 adult subjects without RBC-related disease undergoing splenectomy (controls), five human spleens perfused ex vivo with Hb- and Hb-RBC, and quantified abnormal RBC by microscopy, spleen-mimetic RBC filtration, and adhesion assays. Spleens were analyzed by immunohistochemistry and transmission electron microscopy (TEM).

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Sporadic venous malformations are genetic conditions primarily caused by somatic gain-of-function mutation of PIK3CA or TEK, an endothelial transmembrane receptor signaling through PIK3CA. Venous malformations are associated with pain, bleedings, thrombosis, pulmonary embolism, esthetic deformities and, in severe cases, life-threatening situations. No authorized medical treatment exists for patients with venous malformations.

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Extranodal NK/T-cell lymphoma (ENKTCL) is an Epstein-Barr virus (EBV)-related neoplasm with male dominance and a poor prognosis. A better understanding of the genetic alterations and their functional roles in ENKTCL could help improve patient stratification and treatments. In this study, we performed a comprehensive genetic analysis of 178 ENKTCL cases to delineate the landscape of mutations, copy number alterations (CNA), and structural variations, identifying 34 driver genes including six previously unappreciated ones, namely, HLA-B, HLA-C, ROBO1, CD58, POT1, and MAP2K1.

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Recent large-scale multiomics studies suggest that genetic factors influence the chemical individuality of donated blood. To examine this concept, we performed metabolomics analyses of 643 blood units from volunteers who donated units of packed red blood cells (RBCs) on 2 separate occasions. These analyses identified carnitine metabolism as the most reproducible pathway across multiple donations from the same donor.

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We describe humans with rare biallelic loss-of-function variants impairing pre-α T cell receptor (pre-TCRα) expression. Low circulating naive αβ T cell counts at birth persisted over time, with normal memory αβ and high γδ T cell counts. Their TCRα repertoire was biased, which suggests that noncanonical thymic differentiation pathways can rescue αβ T cell development.

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Red blood cells (RBC) transfusion is used to alleviate symptoms and prevent complications in anemic patients by restoring oxygen delivery to tissues. RBC transfusion efficacy, that can be measured by a rise in hemoglobin (Hb) concentration, is influenced by donor-, product-, and recipient-related characteristics. In some studies, severe pre-transfusion anemia is associated with a greater than expected Hb increment following transfusion but the biological mechanism underpinning this relationship remains poorly understood.

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Hemifacial myohyperplasia (HFMH) is a rare cause of facial asymmetry exclusively involving facial muscles. The underlying cause and the mechanism of disease progression are unknown. Here, we identified a somatic gain-of-function mutation of PIK3CA in five pediatric patients with HFMH.

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Article Synopsis
  • Scientists found that malaria parasites, like Plasmodium falciparum, make red blood cells stiff so they can be removed by the spleen.
  • * They tested over 13,000 compounds and found 82 that could help stop malaria from spreading.
  • * Two drugs, NITD609 and TD-6450, were shown to be safe and effective in lab tests, and they might soon be tested in people.
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Background: On activation, mast cells rapidly release preformed inflammatory mediators from large cytoplasmic granules via regulated exocytosis. This acute degranulation is followed by a late activation phase involving synthesis and secretion of cytokines, growth factors, and other inflammatory molecules via the constitutive pathway that remains ill defined.

Objective: We investigated the role for an insulin-responsive vesicle-like endosomal compartment, marked by insulin-regulated aminopeptidase (IRAP), in the secretion of TNF-α and IL-6 in mast cells and macrophages.

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Article Synopsis
  • - Related Overgrowth Syndrome (PROS) is a genetic disorder linked to mutations that disrupt normal growth and metabolic functions, with significant implications for adipose (fat) tissue and endocrine systems.
  • - Researchers developed a mouse model simulating the disorder's symptoms, revealing how specific mutations lead to insulin resistance, abnormal liver function, and a metabolic shift similar to cancer cells.
  • - The study found that the drug alpelisib can effectively reduce adipose tissue overgrowth and correct metabolic dysfunctions in both the mouse models and in human patients.
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Pannexin 1 (PANX1) was proposed to drive ATP release from red blood cells (RBCs) in response to stress conditions. Stomatin, a membrane protein regulating mechanosensitive channels, has been proposed to modulate PANX1 activity in non-erythroid cells. To determine whether stomatin modulates PANX1 activity in an erythroid context, we have (i) assessed the in situ stomatin-PANX1 interaction in RBCs, (ii) measured PANX1-stimulated activity in RBCs expressing stomatin or from OverHydrated Hereditary Stomatocytosis (OHSt) patients lacking stomatin, and in erythroid K562 cells invalidated for stomatin.

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Background: Schistocyte counts are a cornerstone of the diagnosis of thrombotic microangiopathy syndrome (TMA). Their manual quantification is complex and alternative automated methods suffer from pitfalls that limit their use. We report a method combining imaging flow cytometry (IFC) and artificial intelligence for the direct label-free and operator-independent quantification of schistocytes in whole blood.

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Gaucher disease (GD) is caused by glucocerebrosidase deficiency leading to the accumulation of sphingolipids in macrophages named "Gaucher's Cells". These cells are characterized by deregulated expression of cell surface markers, abnormal secretion of inflammatory cytokines, and iron sequestration. These cells are known to infiltrate tissues resulting in hematological manifestations, splenomegaly, and bone diseases.

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Article Synopsis
  • - Targeting immune checkpoints like PD1 has improved survival for some cancer patients but many still experience relapse or do not respond to treatments.
  • - Neuropilin-1 (NRP1) is identified as a potential immune checkpoint co-receptor that influences CD8 T cell activity in fighting tumors.
  • - Research indicates that NRP1 enhances PD-1 activity and is linked to poorer outcomes in patients with metastatic melanoma treated with anti-PD1 therapies, suggesting it could be a target to improve treatment effectiveness.
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Article Synopsis
  • * Research revealed two patterns of immune response: one with reduced HLA-I expression linked to a suppressive tumor environment and poor prognosis, and another with preserved HLA-I that showed signs of effective immune activity and better outcomes.
  • * The study suggests that HLA-I expression at relapse is a result of immune subversion initiated by BCG, rather than just a consequence of immune editing, highlighting the importance of HLA-I testing for guiding treatment options.
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Refrigerated storage of red cell concentrates before transfusion is associated with progressive alterations of red blood cells (RBC). Small RBC (type III echinocytes, sphero-echinocytes, and spherocytes) defined as storage-induced micro-erythrocytes (SME) appear during pretransfusion storage. SME accumulate with variable intensity from donor to donor, are cleared rapidly after transfusion, and their proportion correlates with transfusion recovery.

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Background: Erythrocytosis is a hematological disorder usually related to hematopoietic stem cell somatic mutations. However, unexplained erythrocytosis remains frequent. In this study, we evaluated the involvement of IgA1, a regulator of erythropoiesis also implicated in IgA nephropathy (IgAN) pathophysiology, in unexplained polycythemia/erythrocytosis (PE) of IgAN patients.

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Permanent availability of red blood cells (RBCs) for transfusion depends on refrigerated storage, during which morphologically altered RBCs accumulate. Among these, a subpopulation of small RBCs, comprising type III echinocytes, spheroechinocytes, and spherocytes and defined as storage-induced microerythrocytes (SMEs), could be rapidly cleared from circulation posttransfusion. We quantified the proportion of SMEs in RBC concentrates from healthy human volunteers and assessed correlation with transfusion recovery, investigated the fate of SMEs upon perfusion through human spleen ex vivo, and explored where and how SMEs are cleared in a mouse model of blood storage and transfusion.

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Objective: Enteropathy-associated T-cell lymphoma (EATL) is a rare but severe complication of coeliac disease (CeD), often preceded by low-grade clonal intraepithelial lymphoproliferation, referred to as type II refractory CeD (RCDII). Knowledge on underlying oncogenic mechanisms remains scarce. Here, we analysed and compared the mutational landscape of RCDII and EATL in order to identify genetic drivers of CeD-associated lymphomagenesis.

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Friedreich ataxia (FRDA) is a frequent autosomal recessive disease caused by a GAA repeat expansion in the FXN gene encoding frataxin, a mitochondrial protein involved in iron-sulfur cluster (ISC) biogenesis. Resulting frataxin deficiency affects ISC-containing proteins and causes iron to accumulate in the brain and heart of FRDA patients. Here we report on abnormal cellular iron homeostasis in FRDA fibroblasts inducing a massive iron overload in cytosol and mitochondria.

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Erythroblast maturation in mammals is dependent on organelle clearance throughout terminal erythropoiesis. We studied the role of the outer mitochondrial membrane protein voltage-dependent anion channel-1 (VDAC1) in human terminal erythropoiesis. We show that short hairpin (shRNA)-mediated downregulation of VDAC1 accelerates erythroblast maturation.

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Background: Red blood cells (RBC) change upon hypothermic conservation, and storage for 6 weeks is associated with the short-term clearance of 15% to 20% of transfused RBCs. Metabolic rejuvenation applied to RBCs before transfusion replenishes energetic sources and reverses most storage-related alterations, but how it impacts RBC circulatory functions has not been fully elucidated.

Study Design And Methods: Six RBC units stored under blood bank conditions were analyzed weekly for 6 weeks and rejuvenated on Day 42 with an adenine-inosine-rich solution.

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