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PI3K-p110δ contributes to antibody responses by macrophages in chronic lymphocytic leukemia.

PI3K-p110δ 有助于慢性淋巴细胞白血病中巨噬细胞的抗体反应。

  • 影响因子:6.08
  • DOI:10.1038/s41375-019-0556-z
  • 作者列表:"Enya Chen YC","Burgess M","Mapp S","Mollee P","Gill D","Blumenthal A","Saunders NA
  • 发表时间:2020-02-01
Abstract

:Fcγ receptor (FcγR) signalling in monocyte derived macrophages from chronic lymphocytic leukaemia (CLL) patients is poorly understood. This signalling pathway is the key determinant of the ability of the macrophages to respond to therapeutic antibodies in current clinical use for CLL. Muted FcγR signalling activity accompanies disease progression and results in resistance to therapeutic antibodies. The molecular mechanisms controlling FcγR signalling and resistance are unknown. Here, we demonstrate that the class I phosphoinositide 3-kinase (PI3K) catalytic subunit p110δ is essential for CLL-derived macrophages to respond to therapeutic antibodies. Inhibition of p110δ in the macrophages reduces FcγR-mediated antibody immune responses. Surprisingly, our studies indicated that FcγR downstream signalling is independent of SYK and BTK activity. Thus, we show that FcγR antibody responses occur via a previously unidentified p110δ-dependent pathway, which is independent of the previously described SYK/BTK activation pathway. These data provide novel insights into the effectors of antibody responses. Our data also provide mechanistic insights into therapy resistance in CLL.

摘要

: 慢性淋巴细胞白血病 (CLL) 患者单核细胞来源的巨噬细胞中的fc γ 受体 (fc γ r) 信号传递知之甚少。该信号传导途径是巨噬细胞在目前CLL临床应用中对治疗性抗体作出反应的能力的关键决定因素。减弱的fc γ r信号传导活性伴随疾病进展并导致对治疗性抗体的抗性。控制fc γ r信号和抗性的分子机制是未知的。在这里,我们证明了I类磷酸肌醇3-激酶 (PI3K) 催化亚基p110δ 对于CLL衍生的巨噬细胞响应治疗性抗体是必需的。巨噬细胞中p110δ 的抑制减少了fc γ r介导的抗体免疫应答。令人惊讶的是,我们的研究表明fc γ r下游信号传导独立于SYK和BTK活性。因此,我们表明fc γ r抗体应答通过先前未鉴定的p110δ 依赖性途径发生,其独立于先前描述的SYK/BTK激活途径。这些数据为抗体应答的效应物提供了新的见解。我们的数据还提供了对CLL治疗耐药的机制见解。

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影响因子:2.86
发表时间:2020-01-01
DOI:10.1097/TA.0000000000002498
作者列表:["Williams J","Merutka N","Meyer D","Bai Y","Prater S","Cabrera R","Holcomb JB","Wade CE","Love JD","Cotton BA"]

METHODS:PURPOSE:Following US military implementation of a cold-stored whole blood program, several US trauma centers have begun incorporating uncrossmatched, group O cold-stored whole blood into civilian trauma resuscitation. We set out to evaluate the safety profile, transfusion reactions events, and impact of low-titer group O whole blood (LTO-WB) at our center. METHODS:In November 2017, we added LTO-WB to each of our helicopters and to our emergency department (ED) refrigerator, alongside that of existing red blood cells and plasma. We collected information on all patients with trauma receiving prehospital or ED transfusion of uncrossed, emergency release blood products between November 2017 and June 2018. Patients were divided into those receiving any LTO-WB and those receiving only red blood cell and or plasma (COMP). Serial hemolysis panels were obtained at 3 hours, 24 hours, and 48 hours. All data were run using STATA 12.1. Statistical significance was set at p < 0.05. RESULTS:One hundred ninety-eight patients received LTO-WB and 152 patients received COMP. There were no differences in age, sex, or mechanism. The LTO-WB patients had higher chest Abbreviated Injury Scale scores (median, 3 vs. 2; p = 0.027), as well as worse arrival base excess (median, -7 vs. -5; p = 0.014) and lactate (5.1 vs. 3.5; p < 0.001). The LTO-WB patients received less post-ED blood products than the COMP patients (median, 0 vs. 3; p = 0.001). There was no difference in survival (LTO-WB, 73%; COMP, 74%; p = 0.805). There were only two suspected transfusion reactions, both in the COMP group (p = 0.061). There was no difference in hemolysis panel values. Controlling for age, severity of injury, and prehospital physiology, LTO-WB was associated with a 53% reduction in post-ED blood product transfusion (odds ratio, 0.47; 0.23-0.94 95% CI; p = 0.033) and two-fold increase in likelihood of survival (odds ratio, 2.19; 1.01-4.76 95% CI; p = 0.047). CONCLUSION:Low-titer group O whole blood has similar evidence of laboratory hemolysis, similar transfusion reaction rates, and is associated with a reduction in post-ED transfusions and increase likelihood of survival. LEVEL OF EVIDENCE:Therapeutic, Level II.

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影响因子:1.33
发表时间:2020-01-01
DOI:10.3233/CH-180541
作者列表:["Chayer B","Allard L","Qin Z","Garcia-Duitama J","Roger L","Destrempes F","Cailhier JF","Denault A","Cloutier G"]

METHODS:BACKGROUND:An enhanced inflammatory response is a trigger to the production of blood macromolecules involved in abnormally high levels of erythrocyte aggregation. OBJECTIVE:This study aimed at demonstrating for the first time the clinical feasibility of a non-invasive ultrasound-based erythrocyte aggregation quantitative measurement method for potential application in critical care medicine. METHODS:Erythrocyte aggregation was evaluated using modeling of the backscatter coefficient with the Structure Factor Size and Attenuation Estimator (SFSAE). SFSAE spectral parameters W (packing factor) and D (mean aggregate diameter) were measured within the antebrachial vein of the forearm and tibial vein of the leg in 50 healthy participants at natural flow and reduced flow controlled by a pressurized bracelet. Blood samples were also collected to measure erythrocyte aggregation ex vivo with an erythroaggregometer (parameter S10). RESULTS:W and Din vivo measurements were positively correlated with the ex vivoS10 index for both measurement sites and shear rates (correlations between 0.35-0.81, p < 0.05). Measurement at low shear rate was found to increase the sensitivity and reliability of this non-invasive measurement method. CONCLUSIONS:We behold that the SFSAE method presents systemic measures of the erythrocyte aggregation level, since results on upper and lower limbs were highly correlated.

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影响因子:2.27
发表时间:2020-02-01
DOI:10.1213/ANE.0000000000004419
作者列表:["Takeshita S","Tanaka KA","Sawa T","Sanda M","Mizobe T","Ogawa S"]

METHODS:BACKGROUND:Incomplete reversal with a recommended 5-g dose of idarucizumab has been reported in patients with excessively high dabigatran concentrations. A timely detection of reversal failure after idarucizumab using whole blood (WB) coagulation testing is clinically useful. The aims of this study were to determine residual dabigatran activity after idarucizumab on thrombin generation (TG) using in vitro supratherapeutic dabigatran models and to compare 4 WB point-of-care tests (activated partial thromboplastin time [aPTT], prothrombin time [PT], and 2 thromboelastometry tests) with the TG results. METHODS:Blood samples from 12 healthy volunteers were spiked in vitro with 0-5000 ng/mL of dabigatran. Dabigatran reversal was evaluated by adding 1000 μg/mL of idarucizumab (Praxbind) to dabigatran-spiked samples, which reflect the administration of 5-g idarucizumab to a 70-kg patient. Residual dabigatran activity was assessed using the calibrated automated TG (Thrombinoscope) in platelet-poor plasma samples. The TG results were compared with WB aPTT (DRIHEMATO APTT-S) and PT (DRIHEMATO PT-S) using CG02N analyzer, thromboelastometry (ROTEM) triggered by ellagic acid (INTEM) and tissue factor (EXTEM). RESULTS:At a therapeutic concentration of dabigatran (200 ng/mL), the lag time was prolonged, and peak TG was decreased. The effects of dabigatran on TG were increased up to 1000 ng/mL, and TG was obliterated at higher supratherapeutic dabigatran levels (P < .001 versus control, respectively). TG was fully restored with idarucizumab when dabigatran was ≤2000 ng/mL, but residual anticoagulant activity was observed at higher dabigatran levels. Dabigatran prolonged WB aPTT and PT concentration dependently, and residual prolongations were observed when idarucizumab was added to 3000 or 5000 ng/mL of dabigatran (P < .001 versus control, respectively). In contrast, both INTEM and EXTEM clotting times were reversed toward reference ranges at all dabigatran concentrations when idarucizumab was added. CONCLUSIONS:Our data indicate that the recommended dose of idarucizumab may not restore TG completely with excessively elevated concentrations of dabigatran. All WB measurements with aPTT, PT, and thromboelastometry predicted supratherapeutic dabigatran concentrations, whereas those tests varied in sensitivity to residual anticoagulant activity after reversal. WB aPTT corresponded well with plasma TG changes among those measurements, but the use of thromboelastometry may overestimate the effect of idarucizumab. Caution should be exercised before extrapolating in vitro point-of-care data to the clinical monitoring of dabigatran reversal.

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