RNAi Screening Uncovers a Synthetic Sick Interaction between CtIP and the BARD1 Tumor Suppressor

Human CtIP is best known for its role in DNA end resection to initiate DNA double-strand break repair by homologous recombination. Recently, CtIP has also been shown to protect reversed replication forks from nucleolytic degradation upon DNA replication stress. However, still little is known about the DNA damage response (DDR) networks that preserve genome integrity and sustain cell survival in the context of CtIP insufficiency. Here, to reveal such potential buffering relationships, we screened a DDR siRNA library in CtIP-deficient cells to identify candidate genes that induce synthetic sickness/lethality (SSL). Our analyses unveil a negative genetic interaction between CtIP and BARD1, the heterodimeric binding partner of BRCA1. We found that simultaneous disruption of CtIP and BARD1 triggers enhanced apoptosis due to persistent replication stress-induced DNA lesions giving rise to chromosomal abnormalities. Moreover, we observed that the genetic interaction between CtIP and BARD1 occurs independently of the BRCA1-BARD1 complex formation and might be, therefore, therapeutical relevant for the treatment of BRCA-defective tumors.Peer reviewe

Assessment of Right Heart Function during Extracorporeal Therapy by Modified Thermodilution in a Porcine Model.

BACKGROUND Veno-arterial extracorporeal membrane oxygenation therapy is a growing treatment modality for acute cardiorespiratory failure. Cardiac output monitoring during veno-arterial extracorporeal membrane oxygenation therapy remains challenging. This study aims to validate a new thermodilution technique during veno-arterial extracorporeal membrane oxygenation therapy using a pig model. METHODS Sixteen healthy pigs were centrally cannulated for veno-arterial extracorporeal membrane oxygenation, and precision flow probes for blood flow assessment were placed on the pulmonary artery. After chest closure, cold boluses of 0.9% saline solution were injected into the extracorporeal membrane oxygenation circuit, right atrium, and right ventricle at different extracorporeal membrane oxygenation flows (4, 3, 2, 1 l/min). Rapid response thermistors in the extracorporeal membrane oxygenation circuit and pulmonary artery recorded the temperature change. After calculating catheter constants, the distributions of injection volumes passing each circuit were assessed and enabled calculation of pulmonary blood flow. Analysis of the exponential temperature decay allowed assessment of right ventricular function. RESULTS Calculated blood flow correlated well with measured blood flow (r = 0.74, P < 0.001). Bias was -6 ml/min [95% CI ± 48 ml/min] with clinically acceptable limits of agreement (668 ml/min [95% CI ± 166 ml/min]). Percentage error varied with extracorporeal membrane oxygenation blood flow reductions, yielding an overall percentage error of 32.1% and a percentage error of 24.3% at low extracorporeal membrane oxygenation blood flows. Right ventricular ejection fraction was 17 [14 to 20.0]%. Extracorporeal membrane oxygenation flow reductions increased end-diastolic and end-systolic volumes with reductions in pulmonary vascular resistance. Central venous pressure and right ventricular ejection fractions remained unchanged. End-diastolic and end-systolic volumes correlated highly (r = 0.98, P < 0.001). CONCLUSIONS Adapted thermodilution allows reliable assessment of cardiac output and right ventricular behavior. During veno-arterial extracorporeal membrane oxygenation weaning, the right ventricle dilates even with stable function, possibly because of increased venous return. : WHAT WE ALREADY KNOW ABOUT THIS TOPIC: Veno-arterial extracorporeal membrane oxygenation is an accepted rescue therapy for patients experiencing severe cardiac or pulmonary failure.Weaning from veno-arterial extracorporeal membrane oxygenation is important for determining next steps in patients' cardiopulmonary care. Assessment of right ventricular function during veno-arterial extracorporeal membrane oxygenation support and weaning is often done using echocardiography, but echocardiographic guidance provides challenges because right ventricular dimensions change with ventricular loading and may not be related to intrinsic right ventricular function. WHAT THIS ARTICLE TELLS US THAT IS NEW In 16 healthy pigs that received veno-arterial extracorporeal membrane oxygenation support via central cannulation, a novel adaptation of thermodilution cardiac output assessment provided reliable estimation of right ventricular cardiac output and right ventricular function.Future studies appear warranted to determine whether this method of modified thermodilution can be used to accurately assess right ventricular output and function during veno-arterial extracorporeal membrane oxygenation support

Integral Assessment of Gas Exchange During Veno-Arterial ECMO - Accuracy and Precision of a Modified Fick Principle in a Porcine Model.

Assessment of native cardiac output during extracorporeal circulation is challenging. We assessed a modified Fick principle under conditions such as deadspace and shunt in 13 anesthetized swine undergoing centrally canulated veno-arterial extracorporeal membrane oxygenation (V-A ECMO, 308 measurement periods) therapy. We assumed that the ratio of carbon dioxide elimination (V̇CO2) or oxygen uptake (V̇O2) between the membrane and native lung corresponds to the ratio of respective blood flows. Unequal ventilation/perfusion (V̇/Q̇) ratios were corrected towards unity. Pulmonary blood flow was calculated and compared to an ultrasonic flow probe on the pulmonary artery with a bias of 99 mL/min (limits of agreement -542 to 741 mL/min) with blood content VO2 and no-shunt, no-deadspace conditions, which showed good trending ability (least significant change from 82 to 129 mL). Shunt conditions led to underestimation of native pulmonary blood flow (bias -395, limits of agreement -1290 to 500 mL/min). Bias and trending further depended on the gas (O2, CO2), and measurement approach (blood content vs. gas phase). Measurements in the gas phase increased the bias (253 [LoA -1357 to 1863 mL/min] for expired V̇O2 bias 482 [LoA -760 to 1724 mL/min] for expired V̇CO2) and could be improved by correction of V̇/Q̇ inequalities. Our results show that common assumptions of the Fick principle in two competing circulations give results with adequate accuracy and may offer a clinically applicable tool. Precision depends on specific conditions. This highlights the complexity of gas exchange in membrane lungs and may further deepen the understanding of V-A ECMO

Optimal fusion rule for distributed detection in clustered wireless sensor networks

We consider distributed detection in a clustered wireless sensor network (WSN) deployed randomly in a large field for the purpose of intrusion detection. The WSN is modeled by a homogeneous Poisson point process. The sensor nodes (SNs) compute local decisions about the intruder’s presence and send them to the cluster heads (CHs). A stochastic geometry framework is employed to derive the optimal cluster-based fusion rule (OCR), which is a weighted average of the local decision sum of each cluster. Interestingly, this structure reduces the effect of false alarm on the detection performance. Moreover, a generalized likelihood ratio test (GLRT) for cluster-based fusion (GCR) is developed to handle the case of unknown intruder’s parameters. Simulation results show that the OCR performance is close to the Chair-Varshney rule. In fact, the latter benchmark can be reached by forming more clusters in the network without increasing the SN deployment intensity. Simulation results also show that the GCR performs very closely to the OCR when the number of clusters is large enough. The performance is further improved when the SN deployment intensity is increased