Uptake of tumor-derived microparticles induces metabolic reprogramming of macrophages in the early metastatic lung.

Pre-metastatic niche formation is a critical step during the metastatic spread of cancer. One way by which primary tumors prime host cells at future metastatic sites is through the shedding of tumor-derived microparticles as a consequence of vascular sheer flow. However, it remains unclear how the uptake of such particles by resident immune cells affects their phenotype and function. Here, we show that ingestion of tumor-derived microparticles by macrophages induces a rapid metabolic and phenotypic switch that is characterized by enhanced mitochondrial mass and function, increased oxidative phosphorylation, and upregulation of adhesion molecules, resulting in reduced motility in the early metastatic lung. This reprogramming event is dependent on signaling through the mTORC1, but not the mTORC2, pathway and is induced by uptake of tumor-derived microparticles. Together, these data support a mechanism by which uptake of tumor-derived microparticles induces reprogramming of macrophages to shape their fate and function in the early metastatic lung.

A National Medical Student Diagnostic Radiology Competition Initiative: Survey and Outcomes of the RadiOlympics.

RATIONALE AND OBJECTIVES: Diagnostic radiology residents may participate in an annual diagnostic imaging tournament that enables residents to engage in friendly competition, network with peers, and practice for board examinations. Medical students would likely enjoy a similar activity, which could increase their interest and knowledge in radiology. Given the lack of initiatives designed to promote competition and learning in medical school radiology education, we designed and implemented the RadiOlympics, the first known national medical student radiology competition in the United States. MATERIAL AND METHODS: A draft version of the competition was emailed to many medical schools in the United States. Medical students interested in assisting with implementation of the competition were invited to a meeting to refine the layout. Ultimately, the format of seven rounds of five questions each and a final round of ten questions all over four months was decided. Questions were written by students and approved by faculty. At the conclusion of the competition, surveys were sent out to gather feedback and gauge how this competition has influenced their interest in radiology. RESULTS: Out of 89 schools that were successfully contacted, 16 schools' radiology clubs agreed to participate, which made up 187 medical students on average per round. At the conclusion of the competition, feedback from students was very positive. Students' confidence in interpreting imaging studies increased after the competition (p < 0.001), although there was not an increased interest in radiology as a career (p = 0.77). CONCLUSION: The RadiOlympics is a national competition that can be successfully organized by medical students for medical students and is an engaging opportunity for medical students to be exposed to radiology.

The e-Autopsy/e-Biopsy: a systematic chart review to increase safety and diagnostic accuracy.

Solving diagnostic errors is difficult and progress on preventing those errors has been slow since the 2015 National Academy of Medicine report. There are several methods used to improve diagnostic and other errors including voluntary reporting; malpractice claims; patient complaints; physician surveys, random quality reviews and audits, and peer review data which usually evaluates single cases and not the systems that allowed the error. Additionally, manual review of charts is often labor intensive and reviewer dependent. In 2010 we developed an e-Autopsy/e-Biopsy (eA/eB) methodology to aggregate cases with quality/safety/diagnostic issues, focusing on a specific population of patients and conditions. By performing a hybrid review process (cases are first filtered using administrative data followed by standardized manual chart reviews) we can efficiently identify patterns of medical and diagnostic error leading to opportunities for system improvements that have improved care for future patients. We present a detailed methodology for eA/eB studies and describe results from three successful studies on different diagnoses (ectopic pregnancy, abdominal aortic aneurysms, and advanced colon cancer) that illustrate our eA/eB process and how it reveals insights into creating systems that reduce diagnostic and other errors. The eA/eB process is innovative and transferable to other healthcare organizations and settings to identify trends in diagnostic error and other quality issues resulting in improved systems of care.

Abnormal Brain Oscillations in Developmental Disorders: Application of Resting State EEG and MEG in Autism Spectrum Disorder and Fragile X Syndrome.

Autism Spectrum Disorder (ASD) and Fragile X Syndrome (FXS) are neurodevelopmental disorders with similar clinical and behavior symptoms and partially overlapping and yet distinct neurobiological origins. It is therefore important to distinguish these disorders from each other as well as from typical development. Examining disruptions in functional connectivity often characteristic of neurodevelopment disorders may be one approach to doing so. This review focuses on EEG and MEG studies of resting state in ASD and FXS, a neuroimaging paradigm frequently used with difficult-to-test populations. It compares the brain regions and frequency bands that appear to be impacted, either in power or connectivity, in each disorder; as well as how these abnormalities may result in the observed symptoms. It argues that the findings in these studies are inconsistent and do not fit neatly into existing models of ASD and FXS, then highlights the gaps in the literature and recommends future avenues of inquiry.

LAR inhibitory peptide promotes recovery of diaphragm function and multiple forms of respiratory neural circuit plasticity after cervical spinal cord injury.

Chondroitin sulfate proteoglycans (CSPGs), up-regulated in and around the lesion after traumatic spinal cord injury (SCI), are key extracellular matrix inhibitory molecules that limit axon growth and consequent recovery of function. CSPG-mediated inhibition occurs via interactions with axonal receptors, including leukocyte common antigen- related (LAR) phosphatase. We tested the effects of a novel LAR inhibitory peptide in rats after hemisection at cervical level 2, a SCI model in which bulbospinal inspiratory neural circuitry originating in the medullary rostral ventral respiratory group (rVRG) becomes disconnected from phrenic motor neuron (PhMN) targets in cervical spinal cord, resulting in persistent partial-to-complete diaphragm paralysis. LAR peptide was delivered by a soaked gelfoam, which was placed directly over the injury site immediately after C2 hemisection and replaced at 1 week post-injury. Axotomized rVRG axons originating in ipsilateral medulla or spared rVRG fibers originating in contralateral medulla were separately assessed by anterograde tracing via AAV2-mCherry injection into rVRG. At 8 weeks post-hemisection, LAR peptide significantly improved ipsilateral hemidiaphragm function, as assessed in vivo with electromyography recordings. LAR peptide promoted robust regeneration of ipsilateral-originating rVRG axons into and through the lesion site and into intact caudal spinal cord to reach PhMNs located at C3-C5 levels. Furthermore, regenerating rVRG axons re-established putative monosynaptic connections with their PhMNs targets. In addition, LAR peptide stimulated robust sprouting of both modulatory serotonergic axons and contralateral-originating rVRG fibers within the PhMN pool ipsilateral/caudal to the hemisection. Our study demonstrates that targeting LAR-based axon growth inhibition promotes multiple forms of respiratory neural circuit plasticity and provides a new peptide-based therapeutic strategy to ameliorate the devastating respiratory consequences of SCI.

Goal-directed actions transiently depend on dorsal hippocampus.

The role of the hippocampus in goal-directed action is currently unclear; studies investigating this issue have produced contradictory results. Here we reconcile these contradictions by demonstrating that, in rats, goal-directed action relies on the dorsal hippocampus, but only transiently, immediately after initial acquisition. Furthermore, we found that goal-directed action also depends transiently on physical context, suggesting a psychological basis for the hippocampal regulation of goal-directed action control.

Lower rates of mortality, readmission and reoperation in patients receiving acupuncture after hip fracture: a population-based analysis.

BACKGROUND: Studies on the effects of acupuncture on mortality and complication rates in hip fracture patients are limited by small sample size and short follow-up time. We aimed to assess the associations of acupuncture use with mortality, readmission and reoperation rates in hip fracture patients using a longitudinal population-based database. METHODS: A retrospective matched cohort study was conducted using data for the years 1996-2012 from Taiwan's National Health Insurance Research Database. Hip fracture patients were divided into an acupuncture group consisting of 292 subjects who received at least 6 acupuncture treatments within 183 days of hip fracture, and a propensity score matched "no acupuncture" group of 876 subjects who did not receive any acupuncture treatment and who functioned as controls. The two groups were compared using survival analysis and competing risk analysis. RESULTS: Compared to non-treated subjects, subjects treated with acupuncture had a lower risk of overall death (hazard ratio (HR): 0.41, 95% confidence interval (CI): 0.24-0.73, p = 0.002), a lower risk of readmission due to medical complications (subdistribution HR (sHR): 0.64, 95% CI: 0.44-0.93, p = 0.019) and a lower risk of reoperation due to surgical complications (sHR: 0.62, 95% CI: 0.40-0.96, p = 0.034). CONCLUSION: This is the first study to suggest that postoperative acupuncture in hip fracture patients is associated with significantly lower mortality, readmission and reoperation rates compared with those of matched controls.

The tenth annual Ion Channel Retreat, Vancouver, Canada, June 25-27, 2012.

Ten years after Aurora Biomed (Vancouver, British Columbia, Canada) hosted the inaugural Ion Channel Retreat, this event is recognized as a leading conference for ion channel researchers. Held annually in Vancouver, this meeting consistently provides an outlet for researchers to share their findings while learning about new concepts, methods, and technologies. Researchers use this forum to discuss and debate a spectrum of topics from ion channel research and technology to drug discovery and safety. The Retreat covered key subjects in the ion channel industry, including ion channels as disease targets, transient receptor protein channels as pain and disease targets, ion channels as pain targets, ion channel structure and function, ion channel screening technologies, cardiac safety and toxicology, and cardiac function and pharmacology.

The ninth annual Ion Channel Retreat, Vancouver, Canada, June 27-29, 2011.

Nine years ago Aurora Biomed Inc. (Vancouver, Canada) committed to gathering the brightest minds and the most innovative research companies at one conference. The Ion Channel Retreat provides a podium for scientific discourse spanning a wide range of ion channel disciplines. This conference has consistently provided a venue for people to share knowledge, exchange ideas, and establish partnerships. This conference continues to expand and grow each year, demonstrating the value of such a conference. Attendees at the 2011 Ion Channel retreat presented ion channel research from 12 different countries, representing research groups located on 5 of the 7 continents. Aurora Biomed's 2011 Retreat covered a variety of topics including Ion Channels as Disease Targets, Ion Channels as Pain Targets, TRP-channels, Ion Channel Screening Technologies, Cardiac Function and Pharmacology, Cardiac Safety and Toxicology, and Structure and Function of Ion Channels.

The eighth annual ion channel retreat, Vancouver, Canada, June 28-30, 2010.

Eight years ago Aurora Biomed Inc. (Vancouver, Canada) committed to gathering the brightest minds and the most innovative research companies at one conference. We sought to provide a podium for scientific discourse spanning a wide range of ion channel disciplines. Since then, researchers from both academia and industry have come together each year to share their knowledge. With attendees from 17 different countries at the 2010 Ion Channel Retreat, this conference continues to grow, and is a testimony to the importance of ion channel research. Aurora Biomed's 2010 Retreat covered a variety of topics, including Ion Channels as Disease Targets, Ion Channels as Pain Targets, K-Channels, TRP-channels, Ion Channel Screening Technologies, Ion Channels in Safety Pharmacology, and Structure and Function of Ion Channels.

Validation of a Rb+ uptake assay for the mouse embryonic stem cell-derived cardiomyocytes Na+, K+ ATPase.

Human Na+, K+ ATPase, an ATP-driven ion transporter, is an emerging drug target for heart-related conditions. Three types of assays including purified enzyme, radiotracer flux, and cold Rb+ flux have been used to determine the activity of this transporter. As an alternative to primary cardiomyocytes, mouse embryonic stem cells-derived cardiomyocytes with functional expression of essential cardiac ion channels were used in the present studies. The results on its pharmacology with digitoxin and ouabain, the 2 well-known cardioglycosides, imply that these cardiomyocytes can be used as a predictive model for the identification of modulators of Na+, K+ ATPase in HTS format.

The sixth annual Ion Channel Retreat Vancouver, Canada, June 23-25, 2008.

The Aurora Biomed-organized annual Ion Channel Retreat occurred in June 2008 and brought together researchers from both academia and industry to share advancements regarding this important field. Topics covered included ion channels as pain targets, ion channels as disease targets, ion channel screening technologies, ion channels in safety screening, and structure and function of ion channels.