Infragravity waves: From driving mechanisms to impacts

Infragravity (hereafter IG) waves are surface ocean waves with frequencies below those of wind-generated “short waves” (typically below 0.04 Hz). Here we focus on the most common type of IG waves, those induced by the presence of groups in incident short waves. Three related mechanisms explain their generation: (1) the development, shoaling and release of waves bound to the short-wave group envelopes (2) the modulation by these envelopes of the location where short waves break, and (3) the merging of bores (breaking wave front, resembling to a hydraulic jump) inside the surfzone. When reaching shallow water (O(1–10 m)), IG waves can transfer part of their energy back to higher frequencies, a process which is highly dependent on beach slope. On gently sloping beaches, IG waves can dissipate a substantial amount of energy through depth-limited breaking. When the bottom is very rough, such as in coral reef environments, a substantial amount of energy can be dissipated through bottom friction. IG wave energy that is not dissipated is reflected seaward, predominantly for the lowest IG frequencies and on steep bottom slopes. This reflection of the lowest IG frequencies can result in the development of standing (also known as stationary) waves. Reflected IG waves can be refractively trapped so that quasi-periodic along-shore patterns, also referred to as edge waves, can develop. IG waves have a large range of implications in the hydro-sedimentary dynamics of coastal zones. For example, they can modulate current velocities in rip channels and strongly influence cross-shore and longshore mixing. On sandy beaches, IG waves can strongly impact the water table and associated groundwater flows. On gently sloping beaches and especially under storm conditions, IG waves can dominate cross-shore sediment transport, generally promoting offshore transport inside the surfzone. Under storm conditions, IG waves can also induce overwash and eventually promote dune erosion and barrier breaching. In tidal inlets, IG waves can propagate into the back-barrier lagoon during the flood phase and induce large modulations of currents and sediment transport. Their effect appears to be smaller during the ebb phase, due to blocking by countercurrents, particularly in shallow systems. On coral and rocky reefs, IG waves can dominate over short-waves and control the hydro-sedimentary dynamics over the reef flat and in the lagoon. In harbors and semi-enclosed basins, free IG waves can be amplified by resonance and induce large seiches (resonant oscillations). Lastly, free IG waves that are generated in the nearshore can cross oceans and they can also explain the development of the Earth's “hum” (background free oscillations of the solid earth)

Targeting the RNA m⁶A reader YTHDF2 selectively compromises cancer stem cells in acute myeloid leukemia

International audienc

Abstract 246: Transendocardial Injections of Allogeneic Mesenchymal Stem Cells Demonstrate Reversal of Left Ventricular Remodeling to Baseline

Background: Mesenchymal stem cells (MSCs) improve ventricular function post MI Hypothesis: Transendocardial stem cell injections (TESI) reverse remodeling in a swine model of chronic ischemic cardiomyopathy (CIC). Methods: Gottingen swine (n=12), underwent a closed-chest, LAD occlusion-reperfusion model to create chronic ischemic cardiomyopathy. Three months post-MI, transendocardial injections of allogeneic MSCs (n=6) or sham injection (control group, n=6) were administered to the infarct and border zones. Cardiac MRI and pressure volume loops were obtained at baseline, during injection, and 6 months post injection. The three dimensional sphericity index (SI) was determined using the formula, SI= (π x LVLA3)/6, where LVLA is the left ventricle long axis length as measured in a 4-chamber long axis cardiac MRI end diastolic frame perpendicular to the line from the annulus of the mitral valve to the apex. Results: The sphericity index increased in both groups 3 months after MI, from 0.268 ± 0.054 to 0.348 ± 0.050 in the sham injection group and 0.277 ± 0.051 to 0.380 ± 0.059 in the TESI group. In the sham injection group, SI remained stable 9 months post sham injections indicative of irreversible remodeling post MI. In contrast, the injection group SI continued to decrease from 0.380 ± 0.059 to 0.346 ± 0.064 and 0.280 ± 0.50 at 3 and 6 months post TESI, respectively. Conclusions: Measurements of SI show that transendocardial stem cell injections of allogeneic MSCs demonstrate the potential to reverse left ventricular remodeling in CIC patients to geometric configurations comparable to their pre-MI shapes

Durable Scar Size Reduction Due to Allogeneic Mesenchymal Stem Cell Therapy Regulates Whole‐Chamber Remodeling

BACKGROUND: Intramyocardial injection of mesenchymal stem cells (MSCs) in chronic ischemic cardiomyopathy is associated with reverse remodeling in experimental models and humans. Here, we tested the hypothesis that allogeneic MSC therapy drives ventricular remodeling by producing durable and progressive scar size reduction in ischemic cardiomyopathy. METHODS AND RESULTS: Gottingen swine (n=12) underwent left anterior descending coronary artery myocardial infarction (MI), and 3 months post‐MI animals received either intramyocardial allogeneic MSC injection (200 mol/L cells; n=6) or left ventricle (LV) catheterization without injection (n=6). Swine were followed with serial cardiac magnetic resonance imaging for 9 months to assess structural and functional changes of the LV. Intramyocardial injection was performed using an integrated imaging platform combining electroanatomical mapping unipolar voltage and 3‐dimensional cardiac magnetic resonance imaging angiography–derived anatomy to accurately target infarct border zone injections. MSC‐treated animals had a 19.62±2.86% reduction in scar size at 3 months postinjection, which progressed to 28.09±2.31% from 3 to 6 months postinjection (P<0.0001). MSC‐treated animals had unchanged end‐diastolic volume (EDV; P=0.08) and end‐systolic volume (ESV; P=0.28) from preinjection to 6 months postinjection, whereas controls had progressive dilatation in both EDV (P=0.0002) and ESV (P=0.0002). In addition, MSC‐treated animals had improved LV sphericity index. Percentage change in infarct size correlated with percentage change in EDV (r=0.68; P=0.01) and ESV (r=0.77; P=0.001). Ejection fraction increased from 29.69±1.68% to 35.85±2.74% at 3 months post‐MSC injection and progressed to 39.02±2.42% 6 months postinjection (P=0.0001), whereas controls had a persistently depressed ejection fraction during follow‐up (P=0.33). CONCLUSION: Intramyocardial injection of allogeneic MSCs leads to a sustained and progressive reduction in infarct size, which in turn drives reverse remodeling and increases in ejection fraction. These findings support ongoing biological activity of cell therapy for substantial periods and suggest optimal end points for future clinical trials

Development of A Core Outcome Set For Infant Gastroesophageal Reflux Disease

OBJECTIVE: In therapeutic trials for infant gastroesophageal reflux disease (GERD), ways to define GERD and measure and report study outcomes vary widely. The aim of this study was to develop a core outcome set (COS) for infant GERD. METHODS: The COS was developed using the Delphi technique, adhering to the Outcome Measures in Rheumatology Initiative 2.0 recommendations. Healthcare professionals (HCPs) (predominantly pediatric gastroenterologists and general pediatricians) and parents of infants (age 0-12 months) with GERD, listed up to 5 primary goals of therapy from their perspective and up to 5 persistent signs or symptoms that would signify inadequate treatment. Outcomes mentioned by >10% of participants were included in 2 shortlists. Next, HCPs and parents rated and prioritized outcomes on these shortlists. Outcomes with the highest rank formed the draft COS. The final COS was created after 2 consensus meetings between an expert panel and patient representatives. RESULTS: In total, 125 of 165 HCPs (76%) and 139 of 143 parents (97%) of infants with GERD completed the first phase. The second phase was completed by 83 of 139 HCPs (60%) and 127 of 142 different parents (89%). Outcomes of these phases were discussed during the consensus meetings and a 9-item COS was formed: "Adequate Growth," "Adequate Relief," "Adverse events,", "Crying," "Evidence of Esophagitis," "Feeding Difficulties," "Hematemesis," "No Escalation of Therapy," and "Sleep Problems." CONCLUSIONS: We developed a COS for infant GERD consisting of 9 items that should minimally be measured in future therapeutic trials to decrease study heterogeneity and ease comparability of results

Abstract 128: Pim1 kinase Overexpression Enhances ckit+ Cardiac Stem Cells Cardioreparative Ability After Intramyocardial Delivery

Background: Pim-1 kinase plays an important role in cell division, survival and commitment towards myocardial lineage. We hypothesized that Pim-1 overexpression in ckit+ cardiac stem cell (CSCs) enhances cardioreparative effects. Methods: Immunosuppressed Yorkshire swine (n=31) received human ckit+ CSCs (n=9), Pim1 modified human ckit+ CSCs (n=9) or PBS (n=13) two weeks after myocardial infarction. Cardiac MRI and PV loops were obtained before and after cell administration. Results: At 8 weeks post transplantation, scar mass (Fig. 1A), viable tissue (Fig. 1B), ejection fraction (Fig. 1C) and stroke work (Fig. 1D) was significantly improved in Pim-1 modified ckit+ CSC compared to control ckit+, while both cell groups showed partial recovery compared to placebo (two way ANOVA, p<0.05). Both cell types similarly reduced preload (end diastolic pressure; Fig. 1E) and afterload (Arterial elastance; Fig 1F) compared to placebo, while only administration of Pim-1 CPCs improved regional contractility at both the infarct (Fig. 1G) and border zones (Fig. 1H). Collectively, mechanoenergetic recoupling was superior in the Pim-1 group compared to ckit+ controls (Cardiac Efficiency; Fig. 1I). Conclusions: Cardioreparative potential of CSCs delivered by intramyocardial injection to infarcted porcine hearts is significantly enhanced by overexpress Pim1, supporting translational development of Pim-1 as a validated genetic modification of CSCs for incorporation into clinical trials

Pim1 Kinase Overexpression Enhances ckit+ Cardiac Stem Cell Cardiac Repair Following Myocardial Infarction in Swine

BackgroundPim1 kinase plays an important role in cell division, survival, and commitment of precursor cells towards a myocardial lineage, and overexpression of Pim1 in ckit+ cardiac stem cells (CSCs) enhances their cardioreparative properties.ObjectivesThe authors sought to validate the effect of Pim1-modified CSCs in a translationally relevant large animal preclinical model of myocardial infarction (MI).MethodsHuman cardiac stem cells (hCSCs, n&nbsp;= 10), hckit+ CSCs overexpressing Pim1 (Pim1+; n&nbsp;= 9), or placebo (n&nbsp;=&nbsp;10) were delivered by intramyocardial injection to immunosuppressed Yorkshire swine (n&nbsp;= 29) 2 weeks after MI. Cardiac magnetic resonance and pressure volume loops were obtained before and after cell administration.ResultsWhereas both hCSCs reduced MI size compared to placebo, Pim1+ cells produced a ∼3-fold greater decrease in scar mass at 8 weeks post-injection compared to hCSCs (-29.2 ± 2.7% vs.&nbsp;-8.4 ± 0.7%; p&nbsp;&lt; 0.003). Pim1+ hCSCs also&nbsp;produced a 2-fold increase of viable mass compared to hCSCs at 8 weeks (113.7 ± 7.2% vs. 65.6 ± 6.8%; p&nbsp;&lt;0.003), and a greater increase in regional contractility in both infarct and border zones (both p&nbsp;&lt; 0.05). Both CSC types significantly increased ejection fraction at 4 weeks but this was only sustained in the Pim1+ group at 8 weeks compared to&nbsp;placebo. Both hCSC and Pim1+ hCSC treatment reduced afterload (p&nbsp;= 0.02 and p&nbsp;= 0.004, respectively). Mechanoenergetic recoupling was significantly greater in the Pim1+ hCSC group (p&nbsp;= 0.005).ConclusionsPim1 overexpression enhanced the effect of intramyocardial delivery of CSCs to infarcted porcine hearts. These findings provide a rationale for genetic modification of stem cells and consequent translation to clinical trials

Abstract 140: Effect of Transendocardial Autologous Cardiac Stem Cells and Bone Marrow Mesenchymal Stem Cells to Reduce Infarct Size and Restore Cardiac Function in a Heart Failure Swine Model

Background: A cell combination of human mesenchymal stem cells (MSCs) and c-kit+ cardiac stem cells (CSCs) improves left ventricular (LV) performance to a greater degree than MSCs alone in post myocardial infarction swine. To advance the development of cell combination therapy, we administered autologous swine cells, and tested the hypothesis that transendocardial autologous CSCs/MSCs produces greater improvement of performance than MSCs in a rigorous model of heart failure due to post infarct LV remodeling. Methods: Gottingen mini-swine (n=28) underwent LAD coronary artery occlusion followed by reperfusion, and allowed to undergo LV remodeling for 90 days. Autologous MSCs were amplified from bone marrow and CSCs from right ventricular biopsies in each swine, and injections of either CSC/MSC combo (1M/200M, n=7), MSCs (200M, n=7), or placebo (Plasmalyte, n=6) were injected to the infarct-border zone via the NOGA system. Cardiac MRI and pressure volume loops were obtained before and after therapy. Results: Both cell groups had substantially reduced scar size (Combo –37.2.9± 5.4% vs MSCs –38.8±7.5% vs placebo −7.2±6.3, P=0.0001) and increased viable tissue (Combo +30.9±7% vs MSCs +41.8±10.5% vs placebo +7.7±4.5, P<0.0001) relative to placebo. Ejection Fraction (EF) improved only in the Combo group (Combo +7.0±2.8 vs MSCs +3.4±1.3 vs placebo +1.2±1.6 EF units, P=0.04). Accompanying this EF restoration was a substantial improvement in the Combo group in stroke volume (Combo +47.2±11.1% vs MSCs +32.6±12.0% vs placebo +10.8±4.5, P<0.0001), cardiac output (Combo +35.9±7.6% vs MSCs 41.9±26.5% vs placebo −16.4±6.6%, P=0.01) and diastolic strain rate (Combo +18.9±8.6% vs MSCs 14.0±8.8% vs placebo −14.9±9.5%, P=0.03). Conclusions: Combination cell therapy and MSCs alone dramatically reduce scar size in a swine model of chronic ischemic cardiomyopathy. In contrast, combination therapy has much greater impact on functional recovery, increasing EF to [near normal] levels. These findings illustrate that interactions between ckit+ CSCs and MSCs result in substantial enhancement in cardiac performance, establish the safety of autologous cell combination strategies, and support the development of an advanced second generation cell therapeutic product

Infragravity waves: from driving mechanisms to impacts

Infragravity (hereafter IG) waves are surface ocean waves with frequencies below those of wind-generated “short waves” (typically below 0.04 Hz). Here we focus on the most common type of IG waves, those induced by the presence of groups in incident short waves. Three related mechanisms explain their generation: (1) the development, shoaling and release of waves bound to the short-wave group envelopes (2) the modulation by these envelopes of the location where short waves break, and (3) the merging of bores (breaking wave front, resembling to a hydraulic jump) inside the surfzone. When reaching shallow water (O(1–10 m)), IG waves can transfer part of their energy back to higher frequencies, a process which is highly dependent on beach slope. On gently sloping beaches, IG waves can dissipate a substantial amount of energy through depth-limited breaking. When the bottom is very rough, such as in coral reef environments, a substantial amount of energy can be dissipated through bottom friction. IG wave energy that is not dissipated is reflected seaward, predominantly for the lowest IG frequencies and on steep bottom slopes. This reflection of the lowest IG frequencies can result in the development of standing (also known as stationary) waves. Reflected IG waves can be refractively trapped so that quasi-periodic along-shore patterns, also referred to as edge waves, can develop. IG waves have a large range of implications in the hydro-sedimentary dynamics of coastal zones. For example, they can modulate current velocities in rip channels and strongly influence cross-shore and longshore mixing. On sandy beaches, IG waves can strongly impact the water table and associated groundwater flows. On gently sloping beaches and especially under storm conditions, IG waves can dominate cross-shore sediment transport, generally promoting offshore transport inside the surfzone. Under storm conditions, IG waves can also induce overwash and eventually promote dune erosion and barrier breaching. In tidal inlets, IG waves can propagate into the back-barrier lagoon during the flood phase and induce large modulations of currents and sediment transport. Their effect appears to be smaller during the ebb phase, due to blocking by countercurrents, particularly in shallow systems. On coral and rocky reefs, IG waves can dominate over short-waves and control the hydro-sedimentary dynamics over the reef flat and in the lagoon. In harbors and semi-enclosed basins, free IG waves can be amplified by resonance and induce large seiches (resonant oscillations). Lastly, free IG waves that are generated in the nearshore can cross oceans and they can also explain the development of the Earth's “hum” (background free oscillations of the solid earth)