Inflammation plays an important role in tissue repair and regeneration. Recent work reveals that inflammatory signaling increases DNA accessibility so as to promote phenotypic fluidity in the ...response to injury.
The prevalence of peripheral arterial disease (PAD) in the United States exceeds 10 million people, and PAD is a significant cause of morbidity and mortality across the globe. PAD is typically caused ...by atherosclerotic obstructions in the large arteries to the leg(s). The most common clinical consequences of PAD include pain on walking (claudication), impaired functional capacity, pain at rest, and loss of tissue integrity in the distal limbs that may lead to lower extremity amputation. Patients with PAD also have higher than expected rates of myocardial infarction, stroke, and cardiovascular death. Despite advances in surgical and endovascular procedures, revascularization procedures may be suboptimal in relieving symptoms, and some patients with PAD cannot be treated because of comorbid conditions. In some cases, relieving obstructive disease in the large conduit arteries does not assure complete limb salvage because of severe microvascular disease. Despite several decades of investigational efforts, medical therapies to improve perfusion to the distal limb are of limited benefit. Whereas recent studies of anticoagulant (eg, rivaroxaban) and intensive lipid lowering (such as PCSK9 proprotein convertase subtilisin/kexin type 9 inhibitors) have reduced major cardiovascular and limb events in PAD populations, chronic ischemia of the limb remains largely resistant to medical therapy. Experimental approaches to improve limb outcomes have included the administration of angiogenic cytokines (either as recombinant protein or as gene therapy) as well as cell therapy. Although early angiogenesis and cell therapy studies were promising, these studies lacked sufficient control groups and larger randomized clinical trials have yet to achieve significant benefit. This review will focus on what has been learned to advance medical revascularization for PAD and how that information might lead to novel approaches for therapeutic angiogenesis and arteriogenesis for PAD.
Peripheral artery disease is a common disorder and a major cause of morbidity and mortality worldwide. Therapy is directed at reducing the risk of major adverse cardiovascular events and at ...ameliorating symptoms. Medical therapy is effective at reducing the incidence of myocardial infarction and stroke to which these patients are prone but is inadequate in relieving limb-related symptoms, such as intermittent claudication, rest pain, and ischemic ulceration. Limb-related morbidity is best addressed with surgical and endovascular interventions that restore perfusion. Current medical therapies have only modest effects on limb blood flow. Accordingly, there is an opportunity to develop medical approaches to restore limb perfusion. Vascular regeneration to enhance limb blood flow includes methods to enhance angiogenesis, arteriogenesis, and vasculogenesis using angiogenic cytokines and cell therapies. We review the molecular mechanisms of these processes; briefly discuss what we have learned from the clinical trials of angiogenic and cell therapies; and conclude with an overview of a potential new approach based upon transdifferentiation to enhance vascular regeneration in peripheral artery disease.
Retroviral overexpression of reprogramming factors (Oct4, Sox2, Klf4, c-Myc) generates induced pluripotent stem cells (iPSCs). However, the integration of foreign DNA could induce genomic ...dysregulation. Cell-permeant proteins (CPPs) could overcome this limitation. To date, this approach has proved exceedingly inefficient. We discovered a striking difference in the pattern of gene expression induced by viral versus CPP-based delivery of the reprogramming factors, suggesting that a signaling pathway required for efficient nuclear reprogramming was activated by the retroviral, but not CPP approach. In gain- and loss-of-function studies, we find that the toll-like receptor 3 (TLR3) pathway enables efficient induction of pluripotency by viral or mmRNA approaches. Stimulation of TLR3 causes rapid and global changes in the expression of epigenetic modifiers to enhance chromatin remodeling and nuclear reprogramming. Activation of inflammatory pathways are required for efficient nuclear reprogramming in the induction of pluripotency.
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▸ TLR3 knockdown reduces the efficiency and yield of human iPSC generation ▸ TLR3 activation enhances human iPSC generation by cell permeant peptides ▸ TLR3 activation enables epigenetic changes to promote an open chromatin state ▸ Innate immune activation enhances nuclear reprogramming and cell plasticity
Efficient reprogramming of somatic cells to pluripotency depends on the activation of innate immune pathways, which cause changes in the expression of epigenetic modifiers and promote chromatin remodeling.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Proton pump inhibitors (PPIs) have been associated with adverse clinical outcomes amongst clopidogrel users after an acute coronary syndrome. Recent pre-clinical results suggest that this risk might ...extend to subjects without any prior history of cardiovascular disease. We explore this potential risk in the general population via data-mining approaches.
Using a novel approach for mining clinical data for pharmacovigilance, we queried over 16 million clinical documents on 2.9 million individuals to examine whether PPI usage was associated with cardiovascular risk in the general population.
In multiple data sources, we found gastroesophageal reflux disease (GERD) patients exposed to PPIs to have a 1.16 fold increased association (95% CI 1.09-1.24) with myocardial infarction (MI). Survival analysis in a prospective cohort found a two-fold (HR = 2.00; 95% CI 1.07-3.78; P = 0.031) increase in association with cardiovascular mortality. We found that this association exists regardless of clopidogrel use. We also found that H2 blockers, an alternate treatment for GERD, were not associated with increased cardiovascular risk; had they been in place, such pharmacovigilance algorithms could have flagged this risk as early as the year 2000.
Consistent with our pre-clinical findings that PPIs may adversely impact vascular function, our data-mining study supports the association of PPI exposure with risk for MI in the general population. These data provide an example of how a combination of experimental studies and data-mining approaches can be applied to prioritize drug safety signals for further investigation.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The authors describe carbon system formulation and simulation characteristics of two new global coupled carbon–climate Earth System Models (ESM), ESM2M and ESM2G. These models demonstrate good ...climate fidelity as described in part I of this study while incorporating explicit and consistent carbon dynamics. The two models differ almost exclusively in the physical ocean component; ESM2M uses the Modular Ocean Model version 4.1 with vertical pressure layers, whereas ESM2G uses generalized ocean layer dynamics with a bulk mixed layer and interior isopycnal layers. On land, both ESMs include a revised land model to simulate competitive vegetation distributions and functioning, including carbon cycling among vegetation, soil, and atmosphere. In the ocean, both models include new biogeochemical algorithms including phytoplankton functional group dynamics with flexible stoichiometry. Preindustrial simulations are spun up to give stable, realistic carbon cycle means and variability. Significant differences in simulation characteristics of these two models are described. Because of differences in oceanic ventilation rates, ESM2M has a stronger biological carbon pump but weaker northward implied atmospheric CO₂ transport than ESM2G. The major advantages of ESM2G over ESM2M are improved representation of surface chlorophyll in the Atlantic and Indian Oceans and thermocline nutrients and oxygen in the North Pacific. Improved tree mortality parameters in ESM2G produced more realistic carbon accumulation in vegetation pools. The major advantages of ESM2M over ESM2G are reduced nutrient and oxygen biases in the southern and tropical oceans.
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BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The physical climate formulation and simulation characteristics of two new global coupled carbon–climate Earth System Models, ESM2M and ESM2G, are described. These models demonstrate similar climate ...fidelity as the Geophysical Fluid Dynamics Laboratory’s previous Climate Model version 2.1 (CM2.1) while incorporating explicit and consistent carbon dynamics. The two models differ exclusively in the physical ocean component; ESM2M uses Modular Ocean Model version 4p1 with vertical pressure layers while ESM2G uses Generalized Ocean Layer Dynamics with a bulk mixed layer and interior isopycnal layers. Differences in the ocean mean state include the thermocline depth being relatively deep in ESM2M and relatively shallow in ESM2G compared to observations. The crucial role of ocean dynamics on climate variability is highlighted in El Niño–Southern Oscillation being overly strong in ESM2M and overly weak in ESM2G relative to observations. Thus, while ESM2G might better represent climate changes relating to total heat content variability given its lack of long-term drift, gyre circulation, and ventilation in the North Pacific, tropical Atlantic, and Indian Oceans, and depth structure in the overturning and abyssal flows, ESM2M might better represent climate changes relating to surface circulation given its superior surface temperature, salinity, and height patterns, tropical Pacific circulation and variability, and Southern Ocean dynamics. The overall assessment is that neither model is fundamentally superior to the other, and that both models achieve sufficient fidelity to allow meaningful climate and earth system modeling applications. This affords the ability to assess the role of ocean configuration on earth system interactions in the context of two state-of-the-art coupled carbon–climate models.
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BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
9.
Endotheliopathy of Obesity Cooke, John P
Circulation,
2020-July-28, Volume:
142, Issue:
4
Journal Article
The Limitless Future of RNA Therapeutics Damase, Tulsi Ram; Sukhovershin, Roman; Boada, Christian ...
Frontiers in bioengineering and biotechnology,
03/2021, Volume:
9
Journal Article
Peer reviewed
Open access
Recent advances in the generation, purification and cellular delivery of RNA have enabled development of RNA-based therapeutics for a broad array of applications. RNA therapeutics comprise a rapidly ...expanding category of drugs that will change the standard of care for many diseases and actualize personalized medicine. These drugs are cost effective, relatively simple to manufacture, and can target previously undruggable pathways. It is a disruptive therapeutic technology, as small biotech startups, as well as academic groups, can rapidly develop new and personalized RNA constructs. In this review we discuss general concepts of different classes of RNA-based therapeutics, including antisense oligonucleotides, aptamers, small interfering RNAs, microRNAs, and messenger RNA. Furthermore, we provide an overview of the RNA-based therapies that are currently being evaluated in clinical trials or have already received regulatory approval. The challenges and advantages associated with use of RNA-based drugs are also discussed along with various approaches for RNA delivery. In addition, we introduce a new concept of hospital-based RNA therapeutics and share our experience with establishing such a platform at Houston Methodist Hospital.
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