Cardiovascular Interactions Tutorial:An Update

The Cardiovascular Interaction (CVI) simulation model was developed by Carl Rothe (1929-2016) as an interactive computer simulation in the form of a tutorial. The original tutorial was based on a five-compartment model (Venous Bed, Right Heart, Lung Bed, Left Heart, and Arterial Bed). This work examines the simulation Dr. Rothe developed based on a six-compartment model (Systemic Veins, Right Ventricle, Pulmonary Arteries, Pulmonary Veins, Left Ventricle, and Systemic Arteries). Both models were originally developed in Visual Basic. Both models have been reimplemented in C# WPF for Windows and in LabVIEW for Windows 10 and Mac OS X

Developmental expression of a functional TASK-1 2P domain K+ channel in embryonic chick heart

<p>Abstract</p> <p>Background</p> <p>Background K⁺channels are the principal determinants of the resting membrane potential (RMP) in cardiac myocytes and thus, influence the magnitude and time course of the action potential (AP).</p> <p>Methods</p> <p>RT-PCR and <it>in situ </it>hybridization are used to study the distribution of TASK-1 and whole-cell patch clamp technique is employed to determine the functional expression of TASK-1 in embryonic chick heart.</p> <p>Results</p> <p>Chicken TASK-1 was expressed in the early tubular heart, then substantially decreased in the ventricles by embryonic day 5 (ED5), but remained relatively high in ED5 and ED11 atria. Unlike TASK-1, TASK-3 was uniformly expressed in heart at all developmental stages. <it>In situ </it>hybridization studies further revealed that TASK-1 was expressed throughout myocardium at Hamilton-Hamburger stages 11 and 18 (S11 & S18) heart. In ED11 heart, TASK-1 expression was more restricted to atria. Consistent with TASK-1 expression data, patch clamp studies indicated that there was little TASK-1 current, as measured by the difference currents between pH 8.4 and pH 7.4, in ED5 and ED11 ventricular myocytes. However, TASK-1 current was present in the early embryonic heart and ED11 atrial myocytes. TASK-1 currents were also identified as 3 μM anandamide-sensitive currents. 3 μM anandamide reduced TASK-1 currents by about 58% in ED11 atrial myocytes. Zn²⁺(100 μM) which selectively inhibits TASK-3 channel at this concentration had no effect on TASK currents. In ED11 ventricle where TASK-1 expression was down-regulated, I_K1was about 5 times greater than in ED11 atrial myocytes.</p> <p>Conclusion</p> <p>Functional TASK-1 channels are differentially expressed in the developing chick heart and TASK-1 channels contribute to background K⁺conductance in the early tubular embryonic heart and in atria. TASK-1 channels act as a contributor to background K⁺current to modulate the cardiac excitability in the embryonic heart that expresses little I_K1.</p

A stochastic model for heart rate fluctuations

Normal human heart rate shows complex fluctuations in time, which is natural, since heart rate is controlled by a large number of different feedback control loops. These unpredictable fluctuations have been shown to display fractal dynamics, long-term correlations, and 1/f noise. These characterizations are statistical and they have been widely studied and used, but much less is known about the detailed time evolution (dynamics) of the heart rate control mechanism. Here we show that a simple one-dimensional Langevin-type stochastic difference equation can accurately model the heart rate fluctuations in a time scale from minutes to hours. The model consists of a deterministic nonlinear part and a stochastic part typical to Gaussian noise, and both parts can be directly determined from the measured heart rate data. Studies of 27 healthy subjects reveal that in most cases the deterministic part has a form typically seen in bistable systems: there are two stable fixed points and one unstable one.Comment: 8 pages in PDF, Revtex style. Added more dat

Osimertinib versus platinum-pemetrexed for patients with EGFR T790M advanced NSCLC and progression on a prior EGFR-tyrosine kinase inhibitor: AURA3 overall survival analysis.

In AURA3 (NCT02151981), osimertinib, a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), significantly prolonged progression-free survival and improved response in patients with EGFR T790M advanced non-small-cell lung cancer (NSCLC) and progression on prior EGFR-TKI treatment. We report the final AURA3 overall survival (OS) analysis.Adult patients were randomized 2 : 1 to osimertinib (80 mg orally, once daily) or pemetrexed plus carboplatin/cisplatin (platinum-pemetrexed) intravenously, every 3 weeks (≤6 cycles). Patients could crossover to osimertinib on progression confirmed by blinded independent central review. OS and safety were secondary end points.A total of 279 patients were randomly assigned to receive osimertinib and 140 to platinum-pemetrexed (136 received treatment). At data cut-off (DCO; 15 March 2019), 188 patients (67%) receiving osimertinib versus 93 (66%) receiving platinum-pemetrexed had died. The hazard ratio (HR) for OS was 0.87 [95% confidence interval (CI) 0.67-1.12; P = 0.277]; the median OS was 26.8 months (95% CI 23.5-31.5) versus 22.5 months (95% CI 20.2-28.8) for osimertinib and platinum-pemetrexed, respectively. The estimated 24- and 36-month survival was 55% versus 43% and 37% versus 30%, respectively. After crossover adjustment, there was an HR of 0.54 (95% CI 0.18-1.6). Time to first subsequent therapy or death showed a clinically meaningful advantage toward osimertinib (HR 0.21, 95% CI 0.16-0.28; P0.001). At DCO, 99/136 (73%) patients in the platinum-pemetrexed arm had crossed over to osimertinib, 66/99 (67%) of whom had died. The most common adverse events possibly related to study treatment were diarrhea (32%; grade ≥3, 1%) and rash (grouped term; 32%; grade ≥3,1%) in the osimertinib arm, versus nausea (47%; grade ≥3, 3%) in the platinum-pemetrexed arm.In patients with T790M advanced NSCLC, no statistically significant benefit in OS was observed for osimertinib versus platinum-pemetrexed, which possibly reflects the high crossover rate of patients from platinum-pemetrexed to osimertinib.ClinicalTrials.gov NCT02151981; https://clinicaltrials.gov/ct2/show/NCT02151981

Measuring the impact of genetic heterogeneity and chromosomal inversions on the efficacy of CRISPR-Cas9 gene drives in different strains of Anopheles gambiae

The human malaria vector Anopheles gambiae is becoming increasingly resistant to insecticides, spurring the development of genetic control strategies. CRISPR-Cas9 gene drives can modify a population by creating double-stranded breaks at highly specific targets, triggering copying of the gene drive into the cut site (‘homing’), ensuring its inheritance. The DNA repair mechanism responsible requires homology between the donor and recipient chromosomes, presenting challenges for the invasion of lab-developed gene drives into wild populations of target species An. gambiae species complex, which show high levels of genome variation. Two gene drives (vas2-5958 and zpg-7280) were introduced into three An. gambiae strains collected across Africa with 5.3-6.6% variation around the target sites, and the effect of this variation on homing was measured. Gene drive homing across different karyotypes of the 2La chromosomal inversion was also assessed. No decrease in gene drive homing was seen despite target site heterology, demonstrating the applicability of gene drives to wild populations

Comparative Study With New Accuracy Metrics for Target Volume Contouring in PET Image Guided Radiation Therapy

[EN] The impact of positron emission tomography (PET) on radiation therapy is held back by poor methods of defining functional volumes of interest. Many new software tools are being proposed for contouring target volumes but the different approaches are not adequately compared and their accuracy is poorly evaluated due to the ill-definition of ground truth. This paper compares the largest cohort to date of established, emerging and proposed PET contouring methods, in terms of accuracy and variability. We emphasize spatial accuracy and present a new metric that addresses the lack of unique ground truth. Thirty methods are used at 13 different institutions to contour functional volumes of interest in clinical PET/CT and a custom-built PET phantom representing typical problems in image guided radiotherapy. Contouring methods are grouped according to algorithmic type, level of interactivity and how they exploit structural information in hybrid images. Experiments reveal benefits of high levels of user interaction, as well as simultaneous visualization of CT images and PET gradients to guide interactive procedures. Method-wise evaluation identifies the danger of over-automation and the value of prior knowledge built into an algorithm.For retrospective patient data and manual ground truth delineation, the authors wish to thank S. Suilamo, K. Lehtio, M. Mokka, and H. Minn at the Department of Oncology and Radiotherapy, Turku University Hospital, Finland. This study was funded by the Finnish Cancer Organisations.Shepherd, T.; Teräs, M.; Beichel, RR.; Boellaard, R.; Bruynooghe, M.; Dicken, V.; Gooding, MJ.... (2012). Comparative Study With New Accuracy Metrics for Target Volume Contouring in PET Image Guided Radiation Therapy. IEEE Transactions on Medical Imaging. 31(12):2006-2024. doi:10.1109/TMI.2012.2202322S20062024311

Differential sensitivity of target genes to translational repression by miR-17~92

MicroRNAs (miRNAs) are thought to exert their functions by modulating the expression of hundreds of target genes and each to a small degree, but it remains unclear how small changes in hundreds of target genes are translated into the specific function of a miRNA. Here, we conducted an integrated analysis of transcriptome and translatome of primary B cells from mutant mice expressing miR-17~92 at three different levels to address this issue. We found that target genes exhibit differential sensitivity to miRNA suppression and that only a small fraction of target genes are actually suppressed by a given concentration of miRNA under physiological conditions. Transgenic expression and deletion of the same miRNA gene regulate largely distinct sets of target genes. miR-17~92 controls target gene expression mainly through translational repression and 5’UTR plays an important role in regulating target gene sensitivity to miRNA suppression. These findings provide molecular insights into a model in which miRNAs exert their specific functions through a small number of key target genesCX is a Pew Scholar in Biomedical Sciences. This study is supported by the PEW Charitable Trusts, Cancer Research Institute, National Institute of Health (R01AI087634, R01AI089854, RC1CA146299, R56AI110403, and R01AI121155 to CX), National Natural Science Foundation of China (31570882 to WHL, 31570883 to NX, 31570911 to GF, 91429301 to JH, 31671428 and 31500665 to YZ), 1000 Young Talents Program of China (K08008 to NX), 100 Talents Program of The Chinese Academy of Sciences (YZ), National Program on Key Basic Research Project of China (2016YFA0501900 to YZ), the Fundamental Research Funds for the Central Universities of China (20720150065 to NX and GF), Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (NRF-2015R1C1A1A01052387 to SGK, NRF-2016R1A4A1010115 to SGK and PHK), and 2016 Research Grant from Kangwon National University (SGK)