An abdominal aortic aneurysm (AAA) is a localized dilation of the aorta located in the abdomen that poses a severe risk of death when ruptured. The cause of AAA is not fully understood, but ...degradation of medial elastin due to elastolytic matrix metalloproteinases is a key step leading to aortic dilation. Current therapeutic interventions are limited to surgical repair to prevent catastrophic rupture. Here, we report the development of injectable supramolecular nanofibers using peptide amphiphile molecules designed to localize to AAA by targeting fragmented elastin, matrix metalloproteinase 2 (MMP-2), and membrane type 1 matrix metalloproteinase. We designed four targeting peptide sequences from X-ray crystallographic data and incorporated them into PA molecules via solid phase peptide synthesis. After coassembling targeted and diluent PAs at different molar ratios, we assessed their ability to form nanofibers using transmission electron microscopy and to localize to AAA in male and female Sprague–Dawley rats using light sheet fluorescence microscopy. We found that three formulations of the PA nanofibers were able to localize to AAA tissue, but the MMP-2 targeting PA substantially outperformed the other nanofibers. Additionally, we demonstrated that the MMP-2 targeting PA nanofibers had an optimal dose of 5 mg (∼12 mg/kg). Our results show that there was not a significant difference in targeting between male and female Sprague–Dawley rats. Given the ability of the MMP-2 targeting PA nanofiber to localize to AAA tissue, future studies will investigate potential diagnostic and targeted drug delivery applications for AAA.
Smoke inhalation injury increases morbidity and mortality. Clinically relevant animal models are necessary for the continued investigation of the pathophysiology of inhalation injury and the ...development of therapeutics. The goal of our research was threefold: 1) to develop a reproducible survival model of smoke inhalation injury in rats that closely resembled our previous mouse model, 2) to validate the rat smoke inhalation injury model using a variety of laboratory techniques, and 3) to compare and contrast our rat model with both the well-established mouse model and previously published rat models to highlight our improvements on smoke delivery and lung injury. Mice and rats were anesthetized, intubated, and placed in custom-built smoke chambers to passively inhale woodchip-generated smoke. Bronchoalveolar lavage fluid (BALF) and lung tissue were collected for confirmatory tests. Lung sections were hematoxylin and eosin stained, lung edema was assessed with wet-to-dry (W/D) ratio, and inflammatory cell infiltration and cytokine elevation were evaluated using flow cytometry, immunohistochemistry, and ELISA. We confirmed that our mouse and rat models of smoke inhalation injury mimic the injury seen after human burn inhalation injury with evidence of pulmonary edema, neutrophil infiltration, and inflammatory cytokine elevation. Interestingly, rats mounted a more severe immunological response compared with mice. In summary, we successfully validated a reliable and clinically translatable survival model of lung injury and immune response in rats and mice and characterized the extent of this injury. These animal models allow for the continued study of smoke inhalation pathophysiology to ultimately develop a better therapeutic.
Since 2019, the global health crisis created by the spread of the COVID-19 coronavirus disease has had widespread human, economic, and social impacts. This crisis has heightened our awareness of ...preexisting health disparities, the slow pace of bureaucratic decision-making, and the increased demands on our health care systems to access, mobilize, and successfully utilize resources. LiveWell, a nonprofit aging services provider, and Bird’s Eye Medical, a for-profit health care organization, were both adept in their ability to leverage community partnerships to meet critical health care needs in their local communities, demonstrating foresight, creativity, and expandable key practice measures. Bird’s Eye Medical and LiveWell developed innovative, community-based approaches to the COVID-19 pandemic, based on purpose and service to their communities, and took quick action in scientific-based practices while prioritizing the needs of vulnerable populations. Two case studies are examined to answer the question, “What can we learn from the successes of the COVID-19 pandemic, and what shifts could we implement to encourage increased cross-sector collaborations?”
The relationship between nanoparticle size, charge, shape, and in vivo biodistribution is of great importance for the rational design and selection of intravenously administered nanoparticles. A ...resource that aids in the selection and design of nanomaterials for this purpose would be a valuable tool. Previous literature reviews have examined narrow categories of nanomaterials or have not statistically analyzed a broad range of nanomaterial literature. Here, data regarding the biodistribution of intravenously administered synthetic and organic nanomaterials in animal models from literature available in PubMed is collected. This work outlines the effect of nanoparticle size, charge, shape, animal sex, and animal disease status on biodistribution of intravenously administered nanomaterials. Particle size and charge are found to significantly and independently influence biodistribution to several organs. Finally, animal sex and disease state are observed to function as effect modifiers for biodistribution.
Recent progress in nanomedicine has necessitated an overview of the effect material characteristics such as size, charge, and shape on biodistribution of intravenously delivered nanomaterials. A resource to aid in design and selection of nanoparticles tailored to specific drug delivery aims is a valuable tool for the field. Here, the ways that particular formulations of nanomaterials or sex/disease status alter material biodistribution are briefly outlined.
Pulmonary hypertension is a highly morbid disease with no cure. Available treatments are limited by systemic adverse effects due to non‐specific biodistribution. Self‐assembled peptide amphiphile ...(PA) nanofibers are biocompatible nanomaterials that can be modified to recognize specific biological markers to provide targeted drug delivery and reduce off‐target toxicity. Here, PA nanofibers that target the angiotensin I‐converting enzyme and the receptor for advanced glycation end‐products (RAGE) are developed, as both proteins are overexpressed in the lung with pulmonary hypertension. It is demonstrated that intravenous delivery of RAGE‐targeted nanofibers containing the targeting epitope LVFFAED (LVFF) significantly accumulated within the lung in a chronic hypoxia‐induced pulmonary hypertension mouse model. Using 3D light sheet fluorescence microscopy, it is shown that LVFF nanofiber localization is specific to the diseased pulmonary tissue with immunofluorescence analysis demonstrating colocalization of the targeted nanofiber to RAGE in the hypoxic lung. Furthermore, biodistribution studies show that significantly more LVFF nanofibers localized to the lung compared to major off‐target organs. Targeted nanofibers are retained within the pulmonary tissue for 24 h after injection. Collectively, these data demonstrate the potential of a RAGE‐targeted nanomaterial as a drug delivery platform to treat pulmonary hypertension.
Peptide amphiphile nanofibers targeted to the receptor for advanced glycation end‐products (RAGE) significantly accumulate within diseased lungs of mice with hypoxia‐induced pulmonary hypertension following intravascular delivery. The targeted nanofibers remain localized to the pulmonary tissue for up to 24 h after injection. PA nanofibers may be effective delivery vehicles to provide targeted therapies for pulmonary hypertension.
Perceived social support has consistently been associated with better psychological well-being, but the pathway(s) through which social support increases positive psychological outcomes (e.g., life ...satisfaction) and reduces negative psychological outcomes (e.g., depression) remain unknown. Potentially, social support may encourage a more balanced, self-forgiving, and positive perspective, which may facilitate better well-being. We investigated the extent to which mindfulness, self-compassion, and savoring accounted for the relation between perceived social support and psychological well-being, as assessed by multiple outcome measures, in college students in the U.S. In Study 1 (N = 1024), greater perceived social support was indirectly related to lower levels of negative psychological well-being outcomes (i.e., depression, anxiety, dysfunctional attitudes) through mindfulness. In Study 2 (N = 228), we replicated and extended these findings. Perceived social support was significantly associated with greater mindfulness, self-compassion, savoring, and positive psychological well-being outcomes (i.e., psychological well-being, subjective happiness), as well as lower levels of negative psychological well-being outcomes (i.e., depression, perceived stress). Furthermore, mindfulness, self-compassion, and savoring each accounted for the association between perceived social support and these psychological well-being outcomes. These findings suggest three pathways through which perceived social support may improve psychological well-being.
CD8
T cells are critical mediators of cytotoxic effector function in infection, cancer and autoimmunity. In cancer and chronic viral infection, CD8
T cells undergo a progressive loss of cytokine ...production and cytotoxicity, a state termed T cell exhaustion. In autoimmunity, autoreactive CD8
T cells retain the capacity to effectively mediate the destruction of host tissues. Although the clinical outcome differs in each context, CD8
T cells are chronically exposed to antigen in all three. These chronically stimulated CD8
T cells share some common phenotypic features, as well as transcriptional and epigenetic programming, across disease contexts. A better understanding of these CD8
T cell states may reveal novel strategies to augment clearance of chronic viral infection and cancer and to mitigate self-reactivity leading to tissue damage in autoimmunity.
T cell dysfunction is a hallmark of many cancers, but the basis for T cell dysfunction and the mechanisms by which antibody blockade of the inhibitory receptor PD-1 (anti-PD-1) reinvigorates T cells ...are not fully understood. Here we show that such therapy acts on a specific subpopulation of exhausted CD8
tumor-infiltrating lymphocytes (TILs). Dysfunctional CD8
TILs possess canonical epigenetic and transcriptional features of exhaustion that mirror those seen in chronic viral infection. Exhausted CD8
TILs include a subpopulation of 'progenitor exhausted' cells that retain polyfunctionality, persist long term and differentiate into 'terminally exhausted' TILs. Consequently, progenitor exhausted CD8
TILs are better able to control tumor growth than are terminally exhausted T cells. Progenitor exhausted TILs can respond to anti-PD-1 therapy, but terminally exhausted TILs cannot. Patients with melanoma who have a higher percentage of progenitor exhausted cells experience a longer duration of response to checkpoint-blockade therapy. Thus, approaches to expand the population of progenitor exhausted CD8
T cells might be an important component of improving the response to checkpoint blockade.
In two parallel randomized trials in patients with MS, ublituximab resulted in lower relapse rates and fewer brain lesions on MRI than teriflunomide over a period of 96 weeks but did not affect ...disability.
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