Biology subjects

Perrot, A.

Publications and source records attributed to Perrot, A..

4 recordsLinked to original sources

bioRxiv2026

Expression profile of CASSIOPEIA patients refines prognostic value of MRD negativity in multiple myeloma

Long-term follow-up of the CASSIOPEIA trial (NCT02541383) demonstrated superior progression-free survival (PFS) with daratumumab, both in combination with bortezomib, thalidomide, and dexamethasone during induction and consolidation, and during maintenance therapy, in transplant- eligible patients newly diagnosed with multiple myeloma (MM). However, outcomes among CASSIOPEIA patients remain heterogeneous across treatment groups. Measurable residual disease (MRD) is a strong indicator of the depth and duration of therapeutic response and is independently associated with both PFS and overall survival (OS), but it does not fully capture the biological diversity of MM. We performed a risk prediction analysis based on transcriptomic subgroups in CASSIOPEIA patients. A subset of 628 patients was characterized using RNA sequencing and consensus clustering identified five transcriptomic subtypes of MM. Long-term follow-up allowed the definition of three transcriptomic risk categories, with estimated 72-month PFS rates of 70%, 51%, and 27% for low, intermediate, and high-risk groups, respectively, among patients who received daratumumab in at least one treatment phase. In these patients, MRD negativity rates after consolidation and six months later were significantly higher in the low and high-risk groups compared with the intermediate-risk group. In the high-risk group, MRD status was not associated with PFS or OS. This suggests that, although daratumumab administered during both the induction/consolidation and maintenance phases improves the clinical outcomes of patients with activation of NSD2 or overexpressing members of the MAF family, highly aggressive minor clones may rapidly expand. These findings emphasize the need for novel therapeutic strategies in this high-risk population.

cancer biology↗

bioRxiv2025

Neutrophil extracellular traps block endogenous and intravenous thrombolysis-induced fibrinolysis in large vessel occlusion acute ischemic stroke

BackgroundIntravenous thrombolysis (IVT) failure in acute ischemic stroke (AIS) due to large vessel occlusion (LVO) is frequent but its causes remain elusive. Several non-exclusive mechanisms have been proposed to explain IVT failure, including failed delivery of tPA and inhibition of its activity. We investigated whether biologically relevant intrathrombus concentrations of t-PA were achieved in failed IVT in patients with LVO AIS, and whether neutrophil extracellular traps (NETs) contributed to IVT failure. MethodsIn this cohort study, a total of 205 thrombi from AIS patients with LVO were analyzed. 83 of these thrombi were compared for tPA content and 53 for their susceptibility to ex vivo thrombolysis according to IVT status. An additional subset of 69 AIS thrombi was used to decipher if and how NETs interfere with intrathrombus fibrinolysis. ResultsAIS thrombi from IVT patients contained more tPA than those from no-IVT patients (0.209 vs 0.093 {micro}g/mg of thrombus, p<0.0001). Plasminogen and tPA in AIS thrombi were found in association with fibrin and NETs. The ability of NETs to bind tPA and plasminogen, titrating them away from fibrin, was confirmed in a microfluidic model of thrombosis. While ex vivo addition of plasminogen did not cause lysis of either no-IVT or IVT thrombi, combining plasminogen with DNase 1 helped translate the increased tPA content of IVT thrombi into increased thrombolysis. We further show that DNase 1 enables tPA- and plasmin-mediated thrombolysis by eliminating fibrinolysis inhibitors from AIS thrombi. ConclusionsThese results indicate that intrathrombus tPA concentrations reached in failed IVT bear a therapeutic potential that is however impaired by NETs, which favor intrathrombus retention of fibrinolysis inhibitors and compete with fibrin for tPA and plasminogen binding. Our results stress the interest of DNase 1 to enhance the efficacy of current IVT tPA regimens. Clinical PerspectiveO_ST_ABSWhat is new?C_ST_ABSO_LIIntravenous thrombolysis increases thrombus tPA content even when it fails to cause arterial recanalization in acute ischemic stroke C_LIO_LIThe fibrinolytic activity of intravenously-administered tPA is blocked by neutrophil extracellular traps in acute ischemic stroke thrombi C_LIO_LINeutrophil extracellular traps participate in thrombolysis resistance by retaining fibrinolysis inhibitors and titrating tPA and plasminogen away from fibrin in acute ischemic stroke thrombi C_LIO_LIDNase 1 can convert increased tPA content into increased fibrinolysis by eliminating NETs-associated fibrinolysis inhibitors in acute ischemic stroke thrombi C_LI 2) What are the clinical implications?O_LIDespite therapeutic failure, biologically significant intrathrombus tPA concentrations are achieved following intravenous thrombolysis at current tPA regimens C_LIO_LISequential administration of DNase 1 prior to intravenous thrombolysis could clear the way for tPA and potentiate its fibrinolytic activity for improved arterial recanalization efficacy C_LI

pathology↗

bioRxiv2024

Inflamed Natural Killer cells with adhesion defects are associated with a poor prognosis in Multiple Myeloma

The promising results obtained with immunotherapeutic approaches for multiple myeloma (MM) call for a better stratification of patients based on immune components. The most pressing being cytotoxic lymphocytes such as Natural Killer (NK) cells that are mandatory for MM surveillance and therapy. In this study, we performed a single cell RNA sequencing analysis of NK cells from 10 MM patients and 10 age/sex matched healthy donors (HD) that revealed important transcriptomic changes in NK cell landscape affecting both the bone marrow and peripheral blood compartment. The frequency of mature cytotoxic "CD56dim" NK cell subsets was reduced in MM patients at the advantage of late-stage NK cell subsets expressing NF{kappa}B and IFN-I inflammatory signatures. These NK cell subsets accumulating in MM patients were characterized by a low CD16 and CD226 expression and poor cytotoxic functions. MM CD16/CD226lo NK cells also had adhesion defects with reduced LFA-1 integrin activation and actin polymerization that may account for their limited effector functions in vitro. Finally, analysis of BM infiltrating NK cells in a retrospective cohort of 177 MM patients from the IFM 2009 trial demonstrated that a high frequency of NK cells and their low CD16 and CD226 expression were associated with a shorter overall survival. Thus, CD16/CD226lo NK cells with reduced effector functions accumulate along MM development and negatively impact patients clinical outcome. Given the growing interest in harnessing NK cells to treat myeloma, this improved knowledge around MM-associated NK cell dysfunction will stimulate the development of more efficient immunotherapeutic drugs against MM. Scientific category: Lymphoid Neoplasia; Immunobiology and Immunotherapy. KEY POINTSO_LIMM patients have increased CD16/CD226low NK cell subsets characterized by "inflammatory" signatures and reduced effector functions. C_LIO_LIThe frequency of CD16/CD226low NK cells correlate with MM patient clinical outcome C_LI

immunology↗

bioRxiv2020

Identification of MYOM2 as a candidate gene in hypertrophic cardiomyopathy and Tetralogy of Fallot and its functional evaluation in the Drosophila heart

The causal genetic underpinnings of congenital heart diseases, which are often complex and with multigenic background, are still far from understood. Moreover, there are also predominantly monogenic heart defects, such as cardiomyopathies, with known disease genes for the majority of cases. In this study, we identified mutations in myomesin 2 (MYOM2) in patients with Tetralogy of Fallot (TOF), the most common cyanotic heart malformation, as well as in patients with hypertrophic cardiomyopathy (HCM), who do not exhibit any mutations in the known disease genes. MYOM2 is a major component of the myofibrillar M-band of the sarcomere and a hub gene within interactions of sarcomere genes. We show that patient-derived cardiomyocytes exhibit myofibrillar disarray and reduced passive force with increasing sarcomere lengths. Moreover, our comprehensive functional analyses in the Drosophila animal model reveal that the so far uncharacterized fly gene CG14964 may be an ortholog of MYOM2, as well as other myosin binding proteins (henceforth named as Drosophila Myomesin and Myosin Binding protein (dMnM)). Its partial loss-of-function or moderate cardiac knockdown results in cardiac dilation, whereas more severely reduced function causes a constricted phenotype and an increase in sarcomere myosin protein. Moreover, compound heterozygous combinations of CG14964 and the sarcomere gene Mhc (MYH6/7) exhibited synergistic genetic interactions. In summary, our results suggest that MYOM2 not only plays a critical role in maintaining robust heart function but may also be a candidate gene for heart diseases such as HCM and TOF, as it is clearly involved in the development of the heart. SUMMARY STATEMENTMYOM2 plays a critical role in establishing or maintaining robust heart function and is a candidate gene for heart diseases such as hypertrophic cardiomyopathy and Tetralogy of Fallot.

genetics↗