A transcriptomic based deconvolution framework for assessing differentiation stages and drug responses of AML

The diagnostic spectrum for AML patients is increasingly based on genetic abnormalities due to their prognostic and predictive value. However, information on the AML blast phenotype regarding their maturational arrest has started to regain importance due to its predictive power for drug responses. Here, we deconvolute 1350 bulk RNA-seq samples from five independent AML cohorts on a single-cell healthy BM reference and demonstrate that the morphological differentiation stages (FAB) could be faithfully reconstituted using estimated cell compositions (ECCs). Moreover, we show that the ECCs reliably predict ex-vivo drug resistances as demonstrated for Venetoclax, a BCL-2 inhibitor, resistance specifically in AML with CD14+ monocyte phenotype. We validate these predictions using LUMC proteomics data by showing that BCL-2 protein abundance is split into two distinct clusters for NPM1-mutated AML at the extremes of CD14+ monocyte percentages, which could be crucial for the Venetoclax dosing patients. Our results suggest that Venetoclax resistance predictions can also be extended to AML without recurrent genetic abnormalities and possibly to MDS-related and secondary AML. Lastly, we show that CD14+ monocytic dominated Ven/Aza treated patients have significantly lower overall survival. Collectively, we propose a framework for allowing a joint mutation and maturation stage modeling that could be used as a blueprint for testing sensitivity for new agents across the various subtypes of AML.This study was funded by a strategic investment of the Leiden University Medical Center, embedded within the Leiden Oncology Center, and executed within the Leiden Center for Computational Oncology. EvdA was funded by a personal grant of the Dutch Research Council (NWO; VENI: 09150161810095).Peer reviewe

In-depth Characterization of Vaccine Breakthrough Infections With SARS-CoV-2 Among Health Care Workers in a Dutch Academic Medical Center

Severe acute respiratory syndrome coronavirus 2 infection after coronavirus disease 2019 vaccination raises concerns about the emergence of vaccine escape variants. Here we characterize 14 breakthrough infections among 5860 fully vaccinated Dutch health care workers ≥14 days after the final dose of vaccination with either BNT162b2, mRNA-1273, or Ad26.COV2.S. These breakthrough infections presented with regular B.1.1.7 (Alpha) and B.1.617.2 (Delta) variants and high viral loads, despite normal vaccine-induced B- and T-cell immune responses detected by live virus neutralization assays and ELISpot. High-risk exposure settings, such as in households, indicate a potential risk of viral transmission despite full vaccination

Abstracts from the 8th International Conference on cGMP Generators, Effectors and Therapeutic Implications

This work was supported by a restricted research grant of Bayer AG

Time poor : rushing decreases the accuracy and reliability of blood pressure measurement technique in pregnancy

Background: In pregnancy, absolute blood pressure (BP) limits define preeclampsia. Therefore, BP in pregnancy should be measured accurately and in accordance with accepted guidelines. Accuracy of BP readings determined by rate of cuff deflation was analyzed. This study also investigated the compliance of clinical staff at Royal Prince Alfred Hospital, Australia, to guidelines for BP measurement. Methods: The study was an observational trial of 98 normotensive antenatal or recently postnatal patients. Two BP readings were taken, each with fast (>5 mm Hg/sec) and slow (2 mm Hg/sec) descent of mercury and compared by Bland-Altman analysis. Also, BP techniques used by junior doctors, specialist obstetricians, and midwives were compared using a 9-point scale. Findings: Australian national guidelines recommend slow descent of mercury. Fast descent underestimated the systolic BP by 9 mm Hg (95% confidence interval [CI], -23 to +5 mm Hg) (p < 0.001). Fast descent measured the iastolic BP within 2 mm Hg (95% CI, -10 to +14 mm Hg) (not different, p = 0.151). Accuracy of fast cuff deflation was 28% for systolic BP and 50% for diastolic BP for <5 mm Hg, and respectively, 64% and 68% for <10 mm Hg, 84% and 80% for <15 mm Hg and 91% and 87% for <20 mm Hg. Compliance with guidelines was greatest for specialists and midwives (p = 0.001) and their most commonly missed feature (76% to100%) was slow cuff deflation. Interpretation: Rapid cuff deflation underestimates the systolic BP compared to accepted guidelines (2 mm Hg/sec). Medical and midwifery staff may not follow accepted guidelines for BP measurement, particularly with regard to rate of cuff deflation. Potential misdiagnosis and under-treatment of patients with hypertension may compromise pregnancy outcomes

Perceptions of post-caesarean section pain and blood pressure in normotensive women

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A transcriptomic based deconvolution framework for assessing differentiation stages and drug responses of AML

The diagnostic spectrum for AML patients is increasingly based on genetic abnormalities due to their prognostic and predictive value. However, information on the AML blast phenotype regarding their maturational arrest has started to regain importance due to its predictive power for drug responses. Here, we deconvolute 1350 bulk RNA-seq samples from five independent AML cohorts on a single-cell healthy BM reference and demonstrate that the morphological differentiation stages (FAB) could be faithfully reconstituted using estimated cell compositions (ECCs). Moreover, we show that the ECCs reliably predict ex-vivo drug resistances as demonstrated for Venetoclax, a BCL-2 inhibitor, resistance specifically in AML with CD14+ monocyte phenotype. We validate these predictions using LUMC proteomics data by showing that BCL-2 protein abundance is split into two distinct clusters for NPM1-mutated AML at the extremes of CD14+ monocyte percentages, which could be crucial for the Venetoclax dosing patients. Our results suggest that Venetoclax resistance predictions can also be extended to AML without recurrent genetic abnormalities and possibly to MDS-related and secondary AML. Lastly, we show that CD14+ monocytic dominated Ven/Aza treated patients have significantly lower overall survival. Collectively, we propose a framework for allowing a joint mutation and maturation stage modeling that could be used as a blueprint for testing sensitivity for new agents across the various subtypes of AML.Pattern Recognition and Bioinformatic

Ground steel target plates in combination with direct transfer of clinical Candida isolates improves frequencies of species-level identification by matrix-assisted laser desorption ionization-time of flight mass spectrometry

Ground steel target plates in combination with direct transfer of clinical Candida isolates improves frequencies of species-level identification by matrix-assisted laser desorption ionization-time of flight mass spectrometry in comparison with polished steel target plates