Evidence from sperm whale clans of symbolic marking in non-human cultures.

Culture, a pillar of the remarkable ecological success of humans, is increasingly recognized as a powerful force structuring nonhuman animal populations. A key gap between these two types of culture is quantitative evidence of symbolic markers-seemingly arbitrary traits that function as reliable indicators of cultural group membership to conspecifics. Using acoustic data collected from 23 Pacific Ocean locations, we provide quantitative evidence that certain sperm whale acoustic signals exhibit spatial patterns consistent with a symbolic marker function. Culture segments sperm whale populations into behaviorally distinct clans, which are defined based on dialects of stereotyped click patterns (codas). We classified 23,429 codas into types using contaminated mixture models and hierarchically clustered coda repertoires into seven clans based on similarities in coda usage; then we evaluated whether coda usage varied with geographic distance within clans or with spatial overlap between clans. Similarities in within-clan usage of both "identity codas" (coda types diagnostic of clan identity) and "nonidentity codas" (coda types used by multiple clans) decrease as space between repertoire recording locations increases. However, between-clan similarity in identity, but not nonidentity, coda usage decreases as clan spatial overlap increases. This matches expectations if sympatry is related to a measurable pressure to diversify to make cultural divisions sharper, thereby providing evidence that identity codas function as symbolic markers of clan identity. Our study provides quantitative evidence of arbitrary traits, resembling human ethnic markers, conveying cultural identity outside of humans, and highlights remarkable similarities in the distributions of human ethnolinguistic groups and sperm whale clans.

Mechanical and interventional support for heart failure with preserved ejection fraction: A review.

INTRODUCTION: Restrictive cardiomyopathy (RCM) and hypertrophic cardiomyopathy (HCM) are two disease processes that are known to progress to heart failure with preserved ejection fraction (HFpEF). Pharmacologic therapies for HFpEF have not improved patient outcomes or reduced mortality in this patient cohort; thus, there continues to be substantial interest in other treatment strategies, including surgical interventions and devices. In this article, we explore and report the current utility of percutaneous therapies and surgically implanted mechanical support in the treatment of patients with HFpEF. RESULTS: Treatment strategies include percutaneous interventions with interatrial shunts, left atrial assist devices (LAADs), and ventricular assist devices (VADs) in various configurations. Although VADs have been employed to treat patients with heart failure with reduced ejection fraction, their efficacy is limited in those with RCM and HCM. A left atrial-to-aortic VAD has been proposed to directly unload the left atrium, but data is limited. Alternatively, a LAAD could be placed in the mitral position and simultaneously unload the left atrium, while filling the left ventricle. CONCLUSION: A left atrial assist device in the mitral position is a promising solution to address the hemodynamic abnormalities in RCM and HCM; these pumps, however, are still under development.

Medical care and first aid: an interassociation consensus framework for organised non-elite sport during the COVID-19 pandemic.

The cessation of amateur and recreational sport has had significant implications globally, impacting economic, social and health facets of population well-being. As a result, there is pressure to resume sport at all levels. The ongoing prevalence of SARS-CoV-2 and subsequent 'second waves' require urgent best practice guidelines to be developed to return recreational (non-elite) sports as quickly as possible while prioritising the well-being of the participants and support staff.This guidance document describes the need for such advice and the process of collating available evidence. Expert opinion is integrated into this document to provide uniform and pragmatic recommendations, thereby optimising on-field and field-side safety for all involved persons, including coaches, first responders and participants.The nature of SARS-CoV-2 transmission means that the use of some procedures performed during emergency care and resuscitation could potentially be hazardous, necessitating the need for guidance on the use of personal protective equipment, the allocation of predetermined areas to manage potentially infective cases and the governance and audit of the process.

Fleet's Geode: A Breakthrough Sensor for Real-Time Ambient Seismic Noise Tomography over DtS-IoT.

As most of the outcropping and shallow mineral deposits have been found, new technology is imperative to finding the hidden critical mineral deposits required to transition to renewable energy. One such new technique, called ambient seismic noise tomography, has shown promise in recent years as a low-cost, low environmental impact method that can image under cover and at depth. Wireless and compact nodal seismic technology has been instrumental to enable industry applications of ambient noise tomography, but these devices are designed for the active seismic reflection method and do not have the required sensitivity at low frequencies for ambient noise tomography, and real-time data transmission in remote locations requires significant infrastructure to be installed. In this paper, we show the development and testing of the Geode-a real-time seismic node purpose-built by Fleet Space Technologies for ambient seismic noise tomography on exploration scales. We discuss the key differences between current nodal technology and the Geode and show results of a field trial where the performance of the Geode is compared with a commercially popular nodal geophone. The use of a 2 Hz high sensitivity geophone and low noise digitiser results in an instrument noise floor that is more than 30 dB lower below 5 Hz than nodes that are commonly used in the industry. The increased sensitivity results in signal-to-noise ratios in the cross-correlation functions in the field trial that are more than double that of commercially available nodal geophone at low frequencies. When considering the full bandwidth of retrievable correlations in our study, using the Geode would reduce the required recording time from 75 h to 32 h to achieve an average signal-to-noise ratio in the cross-correlation functions of 10. We also discuss the integration of a real-time direct-to-satellite Internet of Things (DtS-IoT) modem in the Geode, which, together with edge processing of seismic data directly on the Geode, enables us to image the subsurface in real-time. During the field trial, the Geodes successfully transmitted more than 90% of the available preprocessed data packets. The Geode is compact enough so that several devices can be carried and installed by one field technician, whilst the array of stations do not require a base station to transmit data to the cloud for further processing. We believe this is the future of passive seismic surveys and will result in faster and more dynamic seismic imaging capabilities analogous to the medical imaging community, increasing the pace at which new mineral deposits are discovered.

A novel method for identifying coded tags recorded on aquatic acoustic monitoring systems.

Aquatic biotelemetry increasingly relies on using acoustic transmitters ('tags') that enable passive detection of tagged animals using fixed or mobile receivers. Both tracking methods are resource-limited, restricting the spatial area in which movements of highly mobile animals can be measured using proprietary detection systems. Transmissions from tags are recorded by underwater noise monitoring systems designed for other purposes, such as cetacean monitoring devices, which have been widely deployed in the marine environment; however, no tools currently exist to decode these detections, and thus valuable additional information on animal movements may be missed. Here, we describe simple hybrid methods, with potentially wide application, for obtaining information from otherwise unused data sources. The methods were developed using data from moored, acoustic cetacean detectors (C-PODs) and towed passive receiver arrays, often deployed to monitor the vocalisations of cetaceans, but any similarly formatted data source could be used. The method was applied to decode tag detections that were found to have come from two highly mobile fish species, bass (Dicentrarchus labrax) and Twaite shad (Alosa fallax), that had been tagged in other studies. Decoding results were validated using test tags; range testing data were used to demonstrate the relative efficiency of these receiver methods in detecting tags. This approach broadens the range of equipment from which acoustic tag detections can be decoded. Novel detections derived from the method could add significant value to past and present tracking studies at little additional cost, by providing new insights into the movement of mobile animals at sea.

Mesenchymal stem cells overexpressing BMP-9 by CRISPR-Cas9 present high in vitro osteogenic potential and enhance in vivo bone formation.

Cell therapy is a valuable strategy for the replacement of bone grafts and repair bone defects, and mesenchymal stem cells (MSCs) are the most frequently used cells. This study was designed to genetically edit MSCs to overexpress bone morphogenetic protein 9 (BMP-9) using Clustered Regularly Interspaced Short Palindromic Repeats/associated nuclease Cas9 (CRISPR-Cas9) technique to generate iMSCs-VPRBMP-9+, followed by in vitro evaluation of osteogenic potential and in vivo enhancement of bone formation in rat calvaria defects. Overexpression of BMP-9 was confirmed by its gene expression and protein expression, as well as its targets Hey-1, Bmpr1a, and Bmpr1b, Dlx-5, and Runx2 and  protein expression of SMAD1/5/8 and pSMAD1/5/8. iMSCs-VPRBMP-9+ displayed significant changes in the expression of a panel of genes involved in TGF-ß/BMP signaling pathway. As expected, overexpression of BMP-9 increased the osteogenic potential of MSCs indicated by increased gene expression of osteoblastic markers Runx2, Sp7, Alp, and Oc, higher ALP activity, and matrix mineralization. Rat calvarial bone defects treated with injection of iMSCs-VPRBMP-9+ exhibited increased bone formation and bone mineral density when compared with iMSCs-VPR- and phosphate buffered saline (PBS)-injected defects. This is the first study to confirm that CRISPR-edited MSCs overexpressing BMP-9 effectively enhance bone formation, providing novel options for exploring the capability of genetically edited cells to repair bone defects.

Biomarkers of Cardiac Stress and Cytokine Release Syndrome in COVID-19: A Review.

PURPOSE OF REVIEW: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) resulted in the coronavirus 2019 (COVID-19) global pandemic. While primarily a respiratory virus, SARS-CoV-2 can cause myocardial injury. The pattern of injury, referred to as acute COVID-19 cardiovascular syndrome (ACovCS), is defined by cardiac troponin leak in the absence of obstructive coronary artery disease. Although the etiology of the injury is unknown, many speculate that a cytokine release syndrome (CRS) may be an important factor. We aim to review recent data concerning markers of cardiac injury in ACovCS and its relation to the CRS. RECENT FINDINGS: Cardiac injury was common in patients hospitalized for COVID-19, with both cardiac troponin and B-type natriuretic peptide (BNP) being elevated in this population. Biomarkers were correlated with illness severity and increased mortality. Cytokines such as IL-6 were more often elevated in patients with ACovCS. Myocarditis evident on cardiac MR following COVID-19 may be associated with cardiac troponin levels. The impact of dexamethasone and remdesivir, two therapies shown to have clinical benefit in COVID-19, on myocardial injury is unknown. Biomarkers of cardiac stress and injury in COVID-19 may be used to stratify risk in the future. Currently, there is no evidence that inhibition of cytokine release will reduce myocardial injury in patients with COVID-19.

Sampling the Variational Posterior with Local Refinement.

Variational inference is an optimization-based method for approximating the posterior distribution of the parameters in Bayesian probabilistic models. A key challenge of variational inference is to approximate the posterior with a distribution that is computationally tractable yet sufficiently expressive. We propose a novel method for generating samples from a highly flexible variational approximation. The method starts with a coarse initial approximation and generates samples by refining it in selected, local regions. This allows the samples to capture dependencies and multi-modality in the posterior, even when these are absent from the initial approximation. We demonstrate theoretically that our method always improves the quality of the approximation (as measured by the evidence lower bound). In experiments, our method consistently outperforms recent variational inference methods in terms of log-likelihood and ELBO across three example tasks: the Eight-Schools example (an inference task in a hierarchical model), training a ResNet-20 (Bayesian inference in a large neural network), and the Mushroom task (posterior sampling in a contextual bandit problem).

RUNX1 and RUNX2 transcription factors function in opposing roles to regulate breast cancer stem cells.

Breast cancer stem cells (BCSCs) are competent to initiate tumor formation and growth and refractory to conventional therapies. Consequently BCSCs are implicated in tumor recurrence. Many signaling cascades associated with BCSCs are critical for epithelial-to-mesenchymal transition (EMT). We developed a model system to mechanistically examine BCSCs in basal-like breast cancer using MCF10AT1 FACS sorted for CD24 (negative/low in BCSCs) and CD44 (positive/high in BCSCs). Ingenuity Pathway Analysis comparing RNA-seq on the CD24-/low versus CD24+/high MCF10AT1 indicates that the top activated upstream regulators include TWIST1, TGFß1, OCT4, and other factors known to be increased in BCSCs and during EMT. The top inhibited upstream regulators include ESR1, TP63, and FAS. Consistent with our results, many genes previously demonstrated to be regulated by RUNX factors are altered in BCSCs. The RUNX2 interaction network is the top significant pathway altered between CD24-/low and CD24+/high MCF10AT1. RUNX1 is higher in expression at the RNA level than RUNX2. RUNX3 is not expressed. While, human-specific quantitative polymerase chain reaction primers demonstrate that RUNX1 and CDH1 decrease in human MCF10CA1a cells that have grown tumors within the murine mammary fat pad microenvironment, RUNX2 and VIM increase. Treatment with an inhibitor of RUNX binding to CBFß for 5 days followed by a 7-day recovery period results in EMT suggesting that loss of RUNX1, rather than increase in RUNX2, is a driver of EMT in early stage breast cancer. Increased understanding of RUNX regulation on BCSCs and EMT will provide novel insight into therapeutic strategies to prevent recurrence.

Ventricular arrhythmias following continuous-flow left ventricular assist device implantation: A systematic review.

Ventricular arrhythmias (VA) are not uncommon after continuous-flow left ventricular assist device (CF-LVAD) implantation. In this systematic review, we sought to identify the patterns of VA that occurred following CF-LVAD implantation and evaluate their outcomes. An electronic search was performed to identify all articles reporting the development of VA following CF-LVAD implantation. VA was defined as any episode of ventricular fibrillation (VF) or sustained (>30 seconds) ventricular tachycardia (VT). Eleven studies were pooled for the analysis that included 393 CF-LVAD patients with VA. The mean patient age was 57 years [95%CI: 54; 61] and 82% [95%CI: 73; 88] were male. Overall, 37% [95%CI: 19; 60] of patients experienced a new onset VA after CF-LVAD implantation, while 60% [95%CI: 51; 69] of patients had a prior history of VA. Overall, 88% of patients [95%CI: 78; 94] were supported on HeartMate II CF-LVAD, 6% [95%CI: 3; 14] on HeartWare HVAD, and 6% [95%CI: 2; 13] on other CF-LVADs. VA was symptomatic in 47% [95%CI: 28; 68] of patients and in 50% [95%CI: 37; 52], early VA (<30 days from CF-LVAD) was observed. The 30-day mortality rate was 7% [95%CI: 5; 11]. Mean follow-up was 22.9 months [95%CI: 4.8; 40.8], during which 27% [95%CI: 17; 39] of patients underwent heart transplantation. In conclusion, approximately a third of patients had new VA following CF-LVAD placement. VA in CF-LVAD patients is often symptomatic, necessitates treatment, and carries a worse prognosis.

Clinical implications of LDH isoenzymes in hemolysis and continuous-flow left ventricular assist device-induced thrombosis.

Pump-induced thrombosis continues to be a major complication of continuous-flow left ventricular assist devices (CF-LVADs), which increases the risks of thromboembolic stroke, peripheral thromboembolism, reduced pump flow, pump failure, cardiogenic shock, and death. This is confounded by the fact that there is currently no direct measure for a proper diagnosis during pump support. Given the severity of this complication and its required treatment, the ability to accurately differentiate CF-LVAD pump thrombosis from other complications is vital. Hemolysis measured by elevated lactate dehydrogenase (LDH) enzyme levels, when there is clinical suspicion of pump-induced thrombosis, is currently accepted as an important metric used by clinicians for diagnosis; however, LDH is a relatively nonspecific finding. LDH exists as five isoenzymes in the body, each with a unique tissue distribution. CF-LVAD pump thrombosis has been associated with elevated serum LDH-1 and LDH-2, as well as decreased LDH-4 and LDH-5. Herein, we review the various isoenzymes of LDH and their utility in differentiating hemolysis seen in CF-LVAD pump thrombosis from other physiologic and pathologic conditions as reported in the literature.

Interassociation consensus recommendations for pitch-side emergency care and personal protective equipment for elite sport during the COVID-19 pandemic.

The COVID-19 pandemic has necessitated many novel responses in healthcare including sport and exercise medicine. The cessation of elite sport almost globally has had significant economic implications and resulted in pressure to resume sport in very controlled conditions. This includes protecting pitch-side medical staff and players from infection. The ongoing prevalence of SARS-CoV-2 and the desire to resume professional sport required urgent best practice guidelines to be developed so that sport could be resumed as safely as possible. This set of best practice recommendations assembles early evidence for managing SARS-CoV-2 and integrates expert opinion to provide a uniform and pragmatic approach to enhance on-field and pitch-side safety for the clinician and player. The nature of SARS-CoV-2 transmission creates new hazards during resuscitation and emergency care and procedures. Recommendations for the use and type of personal protective equipment during on-field or pitch-side emergency medical care is provided based on the clinical scenario and projected risk of viral transmission.

RUNX1-dependent mechanisms in biological control and dysregulation in cancer.

The RUNX1 transcription factor has recently been shown to be obligatory for normal development. RUNX1 controls the expression of genes essential for proper development in many cell lineages and tissues including blood, bone, cartilage, hair follicles, and mammary glands. Compromised RUNX1 regulation is associated with many cancers. In this review, we highlight evidence for RUNX1 control in both invertebrate and mammalian development and recent novel findings of perturbed RUNX1 control in breast cancer that has implications for other solid tumors. As RUNX1 is essential for definitive hematopoiesis, RUNX1 mutations in hematopoietic lineage cells have been implicated in the etiology of several leukemias. Studies of solid tumors have revealed a context-dependent function for RUNX1 either as an oncogene or a tumor suppressor. These RUNX1 functions have been reported for breast, prostate, lung, and skin cancers that are related to cancer subtypes and different stages of tumor development. Growing evidence suggests that RUNX1 suppresses aggressiveness in most breast cancer subtypes particularly in the early stage of tumorigenesis. Several studies have identified RUNX1 suppression of the breast cancer epithelial-to-mesenchymal transition. Most recently, RUNX1 repression of cancer stem cells and tumorsphere formation was reported for breast cancer. It is anticipated that these new discoveries of the context-dependent diversity of RUNX1 functions will lead to innovative therapeutic strategies for the intervention of cancer and other abnormalities of normal tissues.

Ethanol Extract of Cissus quadrangularis Enhances Osteoblast Differentiation and Mineralization of Murine Pre-Osteoblastic MC3T3-E1 Cells.

Traditional medicinal literature and previous studies have reported the possible role of Cissus quadrangularis (CQ) as an anti-osteoporotic agent. This study examines the effectiveness of CQ in promoting osteoblast differentiation of the murine pre-osteoblast cell line, MC3T3-E1. Ethanolic extract of CQ (CQ-E) was found to affect growth kinetics of MC3T3-E1 cells in a dosage-dependent manner. High concentrations of CQ-E (more than 10 µg/ml) have particularly adverse effects, while lower concentrations of 0.1 and 1 µg/ml were non-toxic and did not affect cell viability. Notably, cell proliferation was significantly increased at the lower concentrations of CQ-E. CQ-E treatment also augmented osteoblast differentiation, as reflected by a substantial increase in expression of the early osteoblast marker ALP activity, and at later stage, by mineralization of extracellular matrix compared to the control group. These findings suggest dose-dependent effect of CQ-E with lower concentrations exhibiting anabolic and osteogenic properties. J. Cell. Physiol. 232: 540-547, 2017. © 2016 Wiley Periodicals, Inc.

Histone H4 Methyltransferase Suv420h2 Maintains Fidelity of Osteoblast Differentiation.

Osteogenic lineage commitment and progression is controlled by multiple signaling pathways (e.g., WNT, BMP, FGF) that converge on bone-related transcription factors. Access of osteogenic transcription factors to chromatin is controlled by epigenetic regulators that generate post-translational modifications of histones ("histone code"), as well as read, edit and/or erase these modifications. Our understanding of the biological role of epigenetic regulators in osteoblast differentiation remains limited. Therefore, we performed next-generation RNA sequencing (RNA-seq) and established which chromatin-related proteins are robustly expressed in mouse bone tissues (e.g., fracture callus, calvarial bone). These studies also revealed that cells with increased osteogenic potential have higher levels of the H4K20 methyl transferase Suv420h2 compared to other methyl transferases (e.g., Suv39h1, Suv39h2, Suv420h1, Ezh1, Ezh2). We find that all six epigenetic regulators are transiently expressed at different stages of osteoblast differentiation in culture, with maximal mRNAs levels of Suv39h1 and Suv39h2 (at day 3) preceding maximal expression of Suv420h1 and Suv420h2 (at day 7) and developmental stages that reflect, respectively, early and later collagen matrix deposition. Loss of function analysis of Suv420h2 by siRNA depletion shows loss of H4K20 methylation and decreased expression of bone biomarkers (e.g., alkaline phosphatase/Alpl) and osteogenic transcription factors (e.g., Sp7/Osterix). Furthermore, Suv420h2 is required for matrix mineralization during osteoblast differentiation. We conclude that Suv420h2 controls the H4K20 methylome of osteoblasts and is critical for normal progression of osteoblastogenesis. J. Cell. Biochem. 118: 1262-1272, 2017. © 2016 Wiley Periodicals, Inc.

Passive acoustic methods for fine-scale tracking of harbour porpoises in tidal rapids.

The growing interest in generating electrical power from tidal currents using tidal turbine generators raises a number of environmental concerns, including the risk that marine mammals might be injured or killed through collision with rotating turbine blades. To understand this risk, information on how marine mammals use tidal rapid habitats and in particular, their underwater movements and dive behaviour is required. Porpoises, which are the most abundant small cetacean at most European tidal sites, are difficult animals to tag, and the limited size of tidal habitats means that any telemetered animal would be likely to spend only a small proportion of time within them. Here, an alternative approach is explored, whereby passive acoustic monitoring (PAM) is used to obtain fine scale geo-referenced tracks of harbour porpoises in tidal rapid areas. Large aperture hydrophone arrays are required to obtain accurate locations of animals from PAM data and automated algorithms are necessary to process the large quantities of acoustic data collected on such systems during a typical survey. Methods to automate localisation, including a method to match porpoise detections on different hydrophones and separate different vocalising animals, and an assessment of the localisation accuracy of the large aperture hydrophone array are presented.

Driving After Microinvasive Total Hip Arthroplasty.

BACKGROUND: Patients undergoing total hip arthroplasty (THA) are often advised to avoid driving for 6 weeks postoperation. This is based on patients having to maintain postoperative hip precautions and studies investigating brake reaction time (BRT) following THA using conventional techniques. The aim of this study was to assess patients' ability to drive in the early postoperative period following microinvasive THA by assessing BRT. METHODS: Hundred consecutive patients undergoing SuperPATH® THA in 2015 who drove automobiles preoperatively were included in this prospective cohort study. BRT was measured preoperatively and at day 1 or 2 postoperation using a driving simulator. A subset of 25 consecutive patients had repeat BRT testing at 2 weeks postoperation. Five BRT measures were taken at each time point. Differences in the patient's mean and best BRT at each time point were assessed using the paired t-test. RESULTS: The study cohort included 50 men and 50 women with mean age 63 years (range 25-86). The mean preoperative BRT was 0.63 s (range 0.43-1.44), with a mean difference of -0.1 s (range -0.57 to 0.33, P < .0001) at day 1 or 2 postoperation. The 2-week mean and best BRTs were also better than paired preoperative readings with a mean improvement of 0.15 s (range -0.78 to -0.004, P < .0001). CONCLUSION: BRT reaches preoperative values by day 2 following microinvasive THA. Patients may be suitable to drive earlier than the previously recommended 6 weeks postoperation.

Oncofetal Epigenetic Bivalency in Breast Cancer Cells: H3K4 and H3K27 Tri-Methylation as a Biomarker for Phenotypic Plasticity.

Alterations in the epigenetic landscape are fundamental drivers of aberrant gene expression that contribute to cancer progression and pathology. Understanding specific modes of epigenetic regulation can be used to identify novel biomarkers or targets for therapeutic intervention to clinically treat solid tumors and leukemias. The bivalent marking of gene promoters by H3K4me3 and H3K27me3 is a primary mechanism to poise genes for expression in pluripotent embryonic stem cells (ESC). In this study we interrogated three well-established mammary cell lines to model epigenetic programming observed among breast cancer subtypes. Evidence is provided for a distinct bivalent signature, activating and repressive histone marks co-residing at the same gene promoter, in the MCF7 (ESR/PGR+) luminal breast cancer cell line. We identified a subset of genes, enriched for developmental pathways that regulate cellular phenotype and signaling, and partially recapitulate the bivalent character observed in ESC. We validated the biological relevance of this "oncofetal epigenetic" signature using data from ESR/PGR+ tumor samples from breast cancer patients. This signature of oncofetal epigenetic control is an informative biomarker and may provide novel therapeutic targets, selective for both recurring and treatment-resistant cancers. J. Cell. Physiol. 231: 2474-2481, 2016. © 2016 Wiley Periodicals, Inc.

Delivering value: provider efforts to improve the quality and reduce the cost of health care.

Growing concern regarding costs of care and health outcomes in the United States has led to widespread calls to address the issue of health care spending. Today, providers across the country are working both to improve the quality and to reduce the cost of health care. These activities span multiple care delivery settings and include care standardization and redesign, shared decision making, palliative care, care coordination, readmission reduction, patient engagement, predictive modeling, and direct cost reduction. These efforts differ from those undertaken in the past because of the availability of information technology tools to collect and analyze data, and because of the emphasis on cost reduction in conjunction with quality improvement. Although the available literature reflects only a small fraction of the provider activities currently in progress, there is cause for hope for achieving a sustainable, innovative, and value-driven health care system.

MicroRNA-378-mediated suppression of Runx1 alleviates the aggressive phenotype of triple-negative MDA-MB-231 human breast cancer cells.

The Runx1 transcription factor, known for its essential role in normal hematopoiesis, was reported in limited studies to be mutated or associated with human breast tumor tissues. Runx1 increases concomitantly with disease progression in the MMTV-PyMT transgenic mouse model of breast cancer. Compelling questions relate to mechanisms that regulate Runx1 expression in breast cancer. Here, we tested the hypothesis that dysregulation of Runx1-targeting microRNAs (miRNAs) allows for pathologic increase of Runx1 during breast cancer progression. Microarray profiling of the MMTV-PyMT model revealed significant downregulation of numerous miRNAs predicted to target Runx1. One of these, miR-378, was inversely correlated with Runx1 expression during breast cancer progression in mice and in human breast cancer cell lines MCF7 and triple-negative MDA-MB-231 that represent early- and late-stage diseases, respectively. MiR-378 is nearly absent in MDA-MB-231 cells. Luciferase reporter assays revealed that miR-378 binds the Runx1 3' untranslated region (3'UTR) and inhibits Runx1 expression. Functionally, we demonstrated that ectopic expression of miR-378 in MDA-MB-231 cells inhibited Runx1 and suppressed migration and invasion, while inhibition of miR-378 in MCF7 cells increased Runx1 levels and cell migration. Depletion of Runx1 in late-stage breast cancer cells resulted in increased expression of both the miR-378 host gene PPARGC1B and pre-miR-378, suggesting a feedback loop. Taken together, our study identifies a novel and clinically relevant mechanism for regulation of Runx1 in breast cancer that is mediated by a PPARGC1B-miR-378-Runx1 regulatory pathway. Our results highlight the translational potential of miRNA replacement therapy for inhibiting Runx1 in breast cancer.