Na+-leak channel, non-selective (NALCN) regulates myometrial excitability and facilitates successful parturition

Background/Aims: Uterine contractility is controlled by electrical signals generated by myometrial smooth muscle cells. Because aberrant electrical signaling may cause inefficient uterine contractions and poor reproductive outcomes, there is great interest in defining the ion channels that regulate uterine excitability. In human myometrium, the Na+ leak channel, non-selective (NALCN) contributes to a gadolinium-sensitive, Na+-dependent leak current. The aim of this study was to determine the role of NALCN in regulating uterine excitability and examine its involvement in parturition. Methods: Wildtype C57BL/6J mice underwent timed-mating and NALCN uterine expression was measured at several time points across pregnancy including pregnancy days 7, 10, 14, 18 and 19. Sharp electrode current clamp was used to measure uterine excitability at these same time points. To determine NALCN’s contribution to myometrial excitability and pregnancy outcomes, we created smooth-muscle-specific NALCN knockout mice by crossing NALCNfx/fx mice with myosin heavy chain Cre (MHCCreeGFP) mice. Parturition outcomes were assessed by observation via surveillance video recording cre control, flox control, smNALCN+/-, and smNALCN-/- mice. Myometrial excitability was compared between pregnancy day 19 flox controls and smNALCN-/- mice. Results: We found that in the mouse uterus, NALCN protein levels were high early in pregnancy, decreased in mid and late pregnancy, and then increased in labor and postpartum. Sharp electrode current clamp recordings of mouse longitudinal myometrial samples from pregnancy days 7, 10, 14, 18, and 19 revealed day-dependent increases in burst duration and interval and decreases in spike density. NALCN smooth muscle knockout mice had reduced myometrial excitability exemplified by shortened action potential bursts, and an increased rate of abnormal labor, including prolonged and dysfunctional labor. Conclusions: Together, our findings demonstrate that the Na+ conducting channel NALCN contributes to the myometrial action potential waveform and is important for successful labor outcomes

Analysis of electrophysiological activation of the uterus during human labor contractions

This cohort study uses electromyometrial imaging to examine the underlying electrophysiological origins of human labor at the myometrium level

Quantification of cervical elasticity during pregnancy based on transvaginal ultrasound imaging and stress measurement

Objective: Strain elastography and shear wave elastography are two commonly used methods to quantify cervical elasticity; however, they have limitations. Strain elastography is effective in showing tissue elasticity distribution in a single image, but the absence of stress information causes difficulty in comparing the results acquired from different imaging sessions. Shear wave elastography is effective in measuring shear wave speed (an intrinsic tissue property correlated with elasticity) in relatively homogeneous tissue, such as in the liver. However, for inhomogeneous tissue in the cervix, the shear wave speed measurement is less robust. To overcome these limitations, we develop a quantitative cervical elastography system by adding a stress sensor to an ultrasound imaging system. Methods: In an imaging session for quantitative cervical elastography, we use the transvaginal ultrasound imaging system to record B-mode images of the cervix showing its deformation and use the stress sensor to record the probe-surface stress simultaneously. We develop a correlation-based automatic feature tracking algorithm to quantify the deformation, from which the strain is quantified. After each imaging session, we calibrate the stress sensor and transform its measurement to true stress. Applying a linear regression to the stress and strain, we obtain an approximation of the cervical Young's modulus. Results: We validate the accuracy and robustness of this elastography system using phantom experiments. Applying this system to pregnant participants, we observe significant softening of the cervix during pregnancy (p-value < 0.001) with the cervical Young's modulus decreasing 3.95% per week. We estimate that geometric mean values of cervical Young's moduli during the first (11 to 13 weeks), second, and third trimesters are 13.07 kPa, 7.59 kPa, and 4.40 kPa, respectively.Comment: 26 pages, 8 figures, 1 tabl

Magnetic resonance imaging of the supra-cervical fetal membrane detects an increased risk of prelabor rupture of membranes

OBJECTIVE: In 10% of term deliveries and 40% of preterm deliveries, the fetal membrane (FM) ruptures before labor. However, the ability to predict these cases of premature rupture of membranes (PROM) and preterm premature rupture of membranes (PPROM) is very limited. In this paper, our objective was to determine whether a prediction method based on T2 weighted magnetic resonance imaging (MRI) of the supra-cervical FM could predict PROM and PPROM. METHODS: This prospective cohort study enrolled 77 women between the 28th and 37th weeks of gestation. Two indicators of fetal membrane defects, including prolapsed depth \u3e5 mm and signal abnormalities, are investigated for our prediction. Fisher\u27s exact test was used to determine whether prolapsed depth \u3e5 mm and/or signal abnormalities were associated with PROM and PPROM. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were calculated for prolapsed depth \u3e5 mm, signal abnormalities, and the combination of prolapsed depth \u3e5 mm and signal abnormalities. RESULT: Among 12 women with PROM (5 preterm and 7 term, prior to labor onset), 9 had membrane prolapse \u3e5 mm and 5 had FM signal abnormalities. Among 65 women with rupture of membranes at term, 2 had membrane prolapse \u3e5 mm and 1 had signal abnormalities. By Fisher\u27s exact test both indicators, membrane prolapse \u3e5 mm and signal abnormalities, were associated with PROM (P\u3c0.001, P\u3c0.001) and PPROM (P=0.001, P\u3c0.001). Additionally, membrane prolapse \u3e5 mm, signal abnormalities, and the combination of the two indicators all demonstrated high specificity for predicting PROM (96.9%, 98.5%, and 100%, respectively) and PPROM (90.3%, 97.2%, and 100%, respectively). CONCLUSION: MRI can distinguish the supra-cervical fetal membran

Computational repurposing of oncology drugs through off‐target drug binding interactions from pharmacological databases

PurposeSystematic repurposing of approved medicines for another indication may accelerate drug development in oncology. We present a strategy combining biomarker testing with drug repurposing to identify new treatments for patients with advanced cancer.MethodsTumours were sequenced with the Illumina TruSight Oncology 500 (TSO-500) platform or the FoundationOne CDx panel. Mutations were screened by two medical oncologists and pathogenic mutations were categorised referencing literature. Variants of unknown significance were classified as potentially pathogenic using plausible mechanisms and computational prediction of pathogenicity. Gain of function (GOF) mutations were evaluated through repurposing databases Probe Miner (PM), Broad Institute Drug Repurposing Hub (Broad Institute DRH) and TOPOGRAPH. GOF mutations were repurposing events if identified in PM, not indexed in TOPOGRAPH and excluding mutations with a known Food and Drug Administration (FDA)-approved biomarker. The computational repurposing approach was validated by evaluating its ability to identify FDA-approved biomarkers. The total repurposable genome was identified by evaluating all possible gene-FDA drug-approved combinations in the PM dataset.ResultsThe computational repurposing approach was accurate at identifying FDA therapies with known biomarkers (94%). Using next-generation sequencing molecular reports (n = 94), a meaningful percentage of patients (14%) could have an off-label therapeutic identified. The frequency of theoretical drug repurposing events in The Cancer Genome Atlas pan-cancer dataset was 73% of the samples in the cohort.ConclusionA computational drug repurposing approach may assist in identifying novel repurposing events in cancer patients with no access to standard therapies. Further validation is needed to confirm a precision oncology approach using drug repurposing. Repurposing identified Food and Drug Administration-approved drug-biomarker combinations with high sensitivity and specificity. In a real-world dataset, repurposing identified novel drug-biomarker combinations in patients who were ineligible for standard therapies or biomarker-matched trials. Preliminary functional validation was demonstrated for two drug-biomarker combinations. Using The Cancer Genome Atlas data, the potential scope of repurposing was identified. imag

In vivo assessment of supra-cervical fetal membrane by MRI 3D CISS: A preliminary study

In approximately 8% of term births and 33% of pre-term births, the fetal membrane (FM) ruptures before delivery

Noninvasive electromyometrial imaging of human uterine maturation during term labor

Electromyometrial imaging (EMMI) was recently developed to image the three-dimensional (3D) uterine electrical activation during contractions noninvasively and accurately in sheep. Herein we describe the development and application of a human EMMI system to image and evaluate 3D uterine electrical activation patterns at high spatial and temporal resolution during human term labor. We demonstrate the successful integration of the human EMMI system during subjects\u27 clinical visits to generate noninvasively the uterine surface electrical potential maps, electrograms, and activation sequence through an inverse solution using up to 192 electrodes distributed around the abdomen surface. Quantitative indices, including the uterine activation curve, are developed and defined to characterize uterine surface contraction patterns. We thus show that the human EMMI system can provide detailed 3D images and quantification of uterine contractions as well as novel insights into the role of human uterine maturation during labor progression

Social disadvantage during pregnancy: Effects on gestational age and birthweight

OBJECTIVE: Whether psychosocial adversity during pregnancy impacts fetal health outcomes at birth remains underexplored. This is a critical issue given significant social disadvantage and psychosocial stress faced by pregnant women worldwide. STUDY DESIGN: Measures of social disadvantage and psychological factors, and medical/reproductive and nutritional health status in pregnant women were obtained at each trimester. Using Structural Equation Modeling (SEM), we investigated the relationship of forms of adversity to each other and to infant gestational age, and birthweight. RESULTS: Among 399 singletons, Social Disadvantage significantly predicted gestational age (p = 0.003), and residual birthweight (p = 0.006). There was a 0.4 week decrease in gestational age and a 3% decrease in birthweight for each standard deviation increase in Social Disadvantage. CONCLUSION: Significant negative effects of social adversity on the developing fetus were found. Notably, these effects emerged despite good prenatal care and after accounting for maternal age and medical reproductive risk factors