Exaggerated release of neutrophil extracellular traps (NETs) along with decreased NET clearance and inability to remove apoptotic cells (efferocytosis) may contribute to sustained inflammation in acute respiratory distress syndrome (ARDS). Recent studies in experimental models of ARDS have revealed the crosstalk between AMP-activated protein kinase (AMPK) and high-mobility group box 1 (HMGB1), which may contribute to effectiveness of efferocytosis, thereby reducing inflammation and ARDS severity.We investigated neutrophil and NET clearance by macrophages from control and ARDS patients and examined how bronchoalveolar lavage (BAL) fluid from control and ARDS patients could affect NET formation and efferocytosis. Metformin (an AMPK activator) and neutralising antibody against HMGB1 were applied to improve efferocytosis and NET clearance.Neutrophils from ARDS patients showed significantly reduced apoptosis. Conversely, NET formation was significantly enhanced in ARDS patients. Exposure of neutrophils to ARDS BAL fluid promoted NET production, while control BAL fluid had no effect. Macrophage engulfment of NETs and apoptotic neutrophils was diminished in ARDS patients. Notably, activation of AMPK in macrophages or neutralisation of HMGB1 in BAL fluid improved efferocytosis and NET clearance.In conclusion, restoration of AMPK activity with metformin or specific neutralisation of HMGB1 in BAL fluid represent promising therapeutic strategies to decrease sustained lung inflammation during ARDS.

BRAF inhibitors target the BRAF-V600E/K mutated kinase, the driver mutation found in 50% of cutaneous melanoma. They give unprecedented anti-tumor responses but acquisition of resistance ultimately limits their clinical benefit. The master regulators driving the expression of resistance-genes remain poorly understood. Here, we demonstrate that the Aryl hydrocarbon Receptor (AhR) transcription factor is constitutively activated in a subset of melanoma cells, promoting the dedifferentiation of melanoma cells and the expression of BRAFi-resistance genes. Typically, under BRAFi pressure, death of BRAFi-sensitive cells leads to an enrichment of a small subpopulation of AhR-activated and BRAFi-persister cells, responsible for relapse. Also, differentiated and BRAFi-sensitive cells can be redirected towards an AhR-dependent resistant program using AhR agonists. We thus identify Resveratrol, a clinically compatible AhR-antagonist that abrogates deleterious AhR sustained-activation. Combined with BRAFi, Resveratrol reduces the number of BRAFi-resistant cells and delays tumor growth. We thus propose AhR-impairment as a strategy to overcome melanoma resistance.

BackgroundManagement of pregnant women at high risk of pre-eclampsia (PE) requires frequent monitoring, with referral to specialized perinatal care centers. Reliable tests are necessary to improve prediction of PE and related complications and to assess disease severity and progression. An imbalance in two biomarkers, soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF), is involved in PE pathogenesis. The sFlt-1 to PlGF ratio is increased in pregnant women before the onset of PE. An elevated ratio is highly predictive of PE, whereas the diagnosis of PE can be ruled out within one week for low ratios. The main objective of this study was to assess whether a low sFlt-1/PlGF ratio, below a cutoff of 38, can predict the absence of PE within one week.MethodsWe performed a prospective, monocentric, observational study to evaluate serum sFlt-1/PlGF ratio (Roche Diagnostics Cobas e411 system) for predicting -PE in a group of 67 high-risk pregnant women (20–37 gestation weeks).ResultsAmong the 67 patients included, 53 had a sFlt-1/PlGF ratio lower than 38; none developed subsequent PE leading to a negative predictive value of 100%. Eight patients developed clinical PE. The positive predictive value was 21% at one week and 18% at four weeks, in accordance with previous studies.ConclusionsThe serum sFlt-1/PlGF ratio showed highly predictive performances for ruling out PE. Using these biomarkers in routine management of PE may improve clinical care and avoid inappropriate hospitalization, which has a significant economic impact.

Follicular Lymphoma (FL) originates in the lymph nodes (LN) and infiltrates bone marrow (BM) early in the course of the disease. BM FL B cells are characterized by a lower cytological grade, a decreased proliferation, and a specific phenotypic and subclonal profile. Mesenchymal stromal cells (MSC) obtained from FL BM display a specific gene expression profile (GEP), including enrichment for a lymphoid-stromal cell signature, and an increased capacity to sustain FL B-cell growth. However, the mechanisms triggering the formation of the medullar FL permissive stromal niche have not been yet identified. In the current work, we demonstrated that FL B cells produced extracellular vesicles (EVs) that could be internalized by BM-MSC, making them more efficient to support FL B-cell survival and quiescence. Accordingly, EVs purified from FL BM plasma activated TGF-b dependent and independent pathways in BM-MSC, modified their GEP, triggering an upregulation of factors classically associated with hematopoietic stem cell niche, including CXCL12 or angiopoietin-1. Moreover, we provided the first characterization of BM FL B-cell GEP, allowing the definition of the landscape of molecular interactions they could engage with EV-primed BM-MSC. This work identified FL-derived EVs as putative mediators of BM stroma polarization and supported further investigation of their clinical interest for targeting the crosstalk between BM-MSC and malignant B cells.

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B-cell non-Hodgkin lymphoma (B-NHL) evolution and treatment are complicated by a high prevalence of relapses primarily due to the ability of malignant B cells to interact with tumor-supportive lymph node (LN) and bone marrow (BM) microenvironments. In particular, progressive alterations of BM stromal cells sustain the survival, proliferation, and drug resistance of tumor B cells during diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and chronic lymphocytic leukemia (CLL). The current review describes how the crosstalk between BM stromal cells and lymphoma tumor cells triggers the establishment of the tumor supportive niche. DLBCL, FL, and CLL display distinct patterns of BM involvement, but in each case tumor-infiltrating stromal cells, corresponding to cancer-associated fibroblasts, exhibit specific phenotypic and functional features promoting the recruitment, adhesion, and survival of tumor cells. Tumor cell-derived extracellular vesicles have been recently proposed as playing a central role in triggering initial induction of tumor-supportive niches, notably within the BM. Finally, the disruption of the BM stroma reprogramming emerges as a promising therapeutic option in B-cell lymphomas. Targeting the crosstalk between BM stromal cells and malignant B cells, either through the inhibition of stroma-derived B-cell growth factors or through the mobilization of clonal B cells outside their supportive BM niche, should in particular be further evaluated as a way to avoid relapses by abrogating resistance niches.

CD8A encodes the CD8α chain of the dimeric CD8 protein, a critical coreceptor of cytotoxic T cells. We report here the comprehensive immunological evaluation of a child with a CD8A missense mutation, providing evidence that CD8 deficiency increases susceptibility to recurrent respiratory infections without interfering with the TCR-mediated proliferation of T cells. These observations expand the known phenotypes associated with CD8 deficiency.

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