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Lipid nanoparticles (LNPs) exhibit remarkable mRNA delivery efficiency, yet their majority accumulate in the liver or spleen after injection. Tissue‐specific mRNA delivery can be achieved through modulating LNP properties, such as tuning PEGylation or varying lipid components systematically. In this paper, a streamlined method is used for incorporating tumor‐targeting peptides into the LNPs; the programmed death ligand 1 (PD‐L1) binding peptides are conjugated to PEGylated lipids via a copper‐free click reaction, and directly incorporated into the LNP composition (Pep LNPs). Notably, Pep LNPs display robust interaction with PD‐L1 proteins, which leads to the uptake of LNPs into PD‐L1 overexpressing cancer cells both in vitro and in vivo. To evaluate anticancer immunotherapy mediated by restoring tumor suppressor, mRNA encoding phosphatase and tensin homolog (PTEN) is delivered via Pep LNPs to PTEN‐deficient triple‐negative breast cancers (TNBCs). Pep LNPs loaded with PTEN mRNA specifically promotes autophagy‐mediated immunogenic cell death in 4T1 tumors, resulting in effective anticancer immune responses. This study highlights the potential of tumor‐targeted LNPs for mRNA‐based cancer therapy. [ABSTRACT FROM AUTHOR]

Background: In South Korea, the number of people with dementia is rising at a worrisome rate, and many of them also have acute myocardial infarction (AMI), a disease with a high mortality rate. Hypothesis: We speculated that dementia and drug compliance have significant impact on the mortality of patients with AMI. Methods: The study derived data from the National Health Insurance Service‐Senior for a retrospective cohort study. The total number of patients diagnosed with AMI for the first time between 2007 and 2013 was 16 835, among whom 2021 had dementia. Medication possession ratio (MPR) was used to assess medication adherence. Results: AMI patients with dementia had unfavorable baseline characteristics; they had significantly higher risk of all‐cause mortality (hazard ratio [HR]: 2.49; 95% confidence interval [CI]: 2.34−2.66; p <.001) and lower MPR (aspirin: 21.9% vs. 42.8%; p <.001). AMI patients were stratified by presence of dementia and medication adherence, and the survival rate was the highest among those with no dementia and good adherence, followed by those with no dementia and poor adherence, those with dementia and good adherence, and those with dementia and poor adherence. The multivariable analysis revealed that dementia (HR: 1.64; 95% CI: 1.53−1.75; p <.001) and poor adherence to medication (HR: 1.60; 95% CI: 1.49−1.71; p <.001) had a significant association with all‐cause mortality in AMI patients. Conclusions: AMI patients with dementia have a higher mortality rate. Their prognosis is negatively affected by their poorer medication adherence than patients without dementia. [ABSTRACT FROM AUTHOR]

At most institutions, food innovation courses do not highlight the role of community culture, a blind spot that otherwise could connect the United Nations 2030 Agenda for Sustainable Development Goals. This study presents a unique approach to teaching food product innovation, incorporating community culture in ideation, prototyping, and storytelling. Through participatory action research, NUTR 435 Experimental Foods at Montana State University partnered with the Confederated Salish and Kootenai Tribes to teach culturally appropriate product innovation. The class visited the food system stakeholders at the Flathead Reservation and conducted focus groups to gather food memories, understand culinary practices, and recognize product preference of the tribal members. Based on the cultural experiences obtained from the community, the students created smoked trout prototypes and developed recommended recipes for using the smoked trout. The recommended recipes used Native ingredients to tell the tribes' food stories. The students were affirmative on the importance of incorporating culture in food innovations in both the pre‐ and post‐semester learning assessments. Yet, after the semester, the students' attitude and knowledge on this topic became more positive and dynamic, focusing on empowering the community in story and identity telling. Future improvements include recommending a preparatory course in Native American food systems, collaborating with a tribal class, encouraging engagement with the tribal partners beyond the class, and implementing policies to guard the cultural property of the tribal communities. This study presents pilot results for food science educators to consider incorporating community culture in their instructions to address food system challenges. [ABSTRACT FROM AUTHOR]

We examine how audit quality perceptions impact debt mispricing in the presence of earnings management. The Big Four auditors (BFAs) and auditor tenure are used as proxies for perceptions of higher quality audits. Debt mispricing means that debtholders charge a lower (higher) cost of debt to a firm with low (high) accrual earnings management (AEM) and high (low) real earnings management (REM). We find that debt mispricing is accentuated (attenuated) by considering the BFA and auditor tenure because debtholders fixate on quality audits curving AEM. For low AEM and REM firms, debt investors place a premium on low AEM with the BFAs/long‐tenured auditors, worsening the mispricing. For high AEM and low REM firms, debt investors impose a "smaller discount" on high AEM with the BFAs/long‐tenured auditors. This study demonstrates that the accentuation (attenuation) of debt mispricing when considering the BFA and auditor tenure occurs mainly if the firm raised only private debt rather than both private and public debt. [ABSTRACT FROM AUTHOR]

Background and Aim: Appropriate bowel cleansing before colonoscopy is an important factor in increasing the detection rate of lesions. Low‐volume polyethylene glycol (PEG) plus ascorbic acid (PEG‐Asc) reduces the dosage of bowel preparation agent, but still presents discomfort to patients. The primary aim of the present study was to compare the efficacy of bowel cleansing between 2 L PEG‐Asc (control) and 1 L PEG‐Asc with bisacodyl suppository (suppository) groups, and the secondary aim was to investigate complications and tolerability between the two groups. Methods: This was a single‐center prospective randomized controlled study. We identified 168 patients scheduled for colonoscopy between August 2017 and January 2018 and randomly assigned them to the control or to the suppository groups. Efficacy of bowel cleansing was assessed using the Boston Bowel Preparation Scale (BBPS), and side‐effects were surveyed using questionnaires. Results: No significant difference was detected in baseline characteristics including insertion and withdrawal times, and adenoma detection rates between the two groups. Total BBPS score was 7.93 ± 1.06 and 7.74 ± 1.02 in the control and suppository groups, respectively (P = 0.22). Incidence of abdominal pain and nausea was not statistically different, whereas that of sleep disturbance and anal discomfort was higher in the control group. (P = 0.00). Conclusions: One liter PEG‐Asc with bisacodyl suppository resulted in an equivalent bowel‐cleansing outcome with reduced patient discomfort compared to 2 L PEG‐Asc. Therefore, PEG‐Asc with bisacodyl suppository represents a potential alternative and increases patient compliance with bowel preparation. [ABSTRACT FROM AUTHOR]

Rubus occidentalis (RO) has beneficial effects on glucose and lipid profiles in vitro. The aim of the study was to investigate RO extract effect on metabolic parameters in prediabetic patients, adopting a 12-week, randomized, double-blind, placebo-controlled trial. Forty-four patients (age 59.0 ± 8.2 years, 70.5% females, HbA1c 5.8 ± 0.4%) were divided into placebo (n = 13), low-dose RO extract (LRE; n = 14), or high-dose RO extract (HRE; n = 17) groups. Either 900 or 1800 mg per day of RO extract was administered orally. Area under the curve for glucose obtained 2 h after a 75-g oral glucose tolerance test was significantly decreased in the HRE group, compared with the placebo group (-28.1 ± 42.4 vs. +13.4 ± 52.6 mg/dL, p < 0.05). Homoeostasis model assessment-B was increased (+17.11 ± 10.69, +5.24 ± 4.10, and +0.86 ± 6.01 in HRE, LRE, and placebo, respectively, p < 0.05). Serum levels of monocyte chemoattractant protein-1 and oxidized low-density lipoprotein were significantly decreased by treatment in a dose-dependent manner (monocyte chemoattractant protein-1: -35.0 ± 21.2, +8.4 ± 18.1, and +24.2 ± 14.5; oxidized low-density lipoprotein: -19.7 ± 8.5, -13.1 ± 7.2, and -2.2 ± 11.0 in the HRE, LRE, and placebo, respectively, p < 0.05). The results support the beneficial effects of RO extract on the control of glycemia and vascular inflammation in prediabetic patients. (ClinicalTrials.gov: NCT01964703). Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

With the increasing demand for instant real-time ultrasound (US) imaging of a specific organ, target-specific and long-circulating ultrasound contrast agents are of special interest. A new species of echogenic hyaluronic acid nanoparticles is presented as an ultralong-acting, liver-specific, US contrast agent that is distinct from conventional gas-filled microbubbles. Using an oil-in-water (O/W) emulsification method, bioinert and hydrophobic perfluoropentane (PFP) is encapsulated as an ultrasound gas precursor into hyaluronic acid nanoparticles (HANPs) using hydrophobic interactions. HANPs are formulated by self-assembly, with amphiphilic hyaluronic acid-5β-cholanic acid (HA-CA) conjugating in aqueous conditions. The resulting echogenic PFP-encapsulated HANPs (Echo-NPs) show solid nanostructures, differentiated from core-empty conventional microbubbles, and exhibiting outstanding physical properties as an ultrasound contrast agent. They are more stable and robust echogenic solid bodies with an in vivo favorable hydrodynamic size and because PFPs vaporize gradually, their expansion process is very slow in body conditions. After several systemic circulations, echo-NPs generated intense and ultralong echo signals for US imaging at the target site. The echogenic properties of Echo-NPs show a significantly increased half-life and echo persistence, compared with conventional microbubbles. The results clearly show that echo-NPs outperform conventional microbubbles in terms of both physical and echogenic in vitro and in vivo properties. [ABSTRACT FROM AUTHOR]

Background Oncolytic adenovirus (Ad)-mediated gene therapy is a promising approach for suppression of primary tumors. Therapeutic efficacy of Ad-mediated gene therapy has been limited by immunogenicity, rapid dissemination of viral progenies into systemic circulation and short duration of biological activity. Polymeric sustained local delivery can overcome many of these challenges to produce a viable therapy with improved outcomes. Methods Silk-elastinlike protein polymer (SELP) hydrogels were used for matrix-mediated delivery of oncolytic Ad, containing short hairpin RNA (shRNA) targeted to C-Met (sh-C-Met), to solid tumors in a nude mouse model of human head and neck cancer. The biological activity of Ad released from SELP hydrogels was examined as a function of time to investigate protective effects on viral activity. Antitumor efficacy and viral distribution were investigated for 3 weeks in tumor-bearing mice. Results The encapsulation of Ad with SELP hydrogels sustained biological activity longer than Ad alone. Ad in SELP matrix showed 1.5-fold greater antitumor efficacy compared to that of naked Ad in human xenograft tumor models. Histological analysis demonstrated that treatment with Ad in a SELP matrix resulted in apoptosis in a wider area of tumor tissue and higher density of Ad infection compared to Ad administered alone. Conclusions Matrix-mediated delivery of Ad-containing shRNA with SELP hydrogels enhances therapeutic efficacy by tumor-selective infection, spatiotemporal control and preservation of biologic activity. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background Signalling cross talk provides a molecular basis for modulating a given signalling pathway by another, and it is often critical for regulating cellular responses elicited by cytokines. Previously, we reported on the critical role of the IFN-α/β signalling complex, generated by spontaneously produced IFN-α/β, in efficient IFN-γ signalling. Results In the present study, we have demonstrated that the IFN-α/β signalling complex also contributes to efficient IL-6 signalling. In fact, IL-6-induced activation of the Stat1 and Stat3 transcription factors is markedly diminished in the absence of the IFN-α/β signalling complex. The induction of several target genes for these factors is also diminished, both in vitro and in vivo. We provide evidence that the cytoplasmic tyrosine residues of IFNAR-1, which remains phosphorylated by a weak IFN-α/β stimulation, provide docking sites for Stat1 and Stat3 to form homo- or heterodimers following IL-6 stimulation. Furthermore, a chemical cross-linking experiment revealed that IFNAR-1 and gp130, a common signal transducer for the IL-6 family of cytokines, exist in close proximity. Conclusions The constitutive weak IFN-α/β signal provides a foundation for strong cellular responses to IL-6, IFN-γ, and possibly other cytokines. Our results also suggest the assembly of cytokine receptor subunits, which may represent a ‘receptosome’-like structure, allowing the unique signalling cross talks to occur. [ABSTRACT FROM AUTHOR]

Macrophages (Mϕs) critically contribute to wound healing by coordinating inflammatory, proliferative, and angiogenic processes. A proper switch from proinflammatory M1 to anti‐inflammatory M2 dominant Mϕs accelerates the wound healing processes leading to favorable wound‐care outcomes. Herein, an exosome‐guided cell reprogramming technique is proposed to directly convert M1 to M2 Mϕs for effective wound management. The M2 Mϕ‐derived exosomes (M2‐Exo) induce a complete conversion of M1 to M2 Mϕs in vitro. The reprogrammed M2 Mϕs turn Arginase (M2‐marker) and iNOS (M1‐marker) on and off, respectively, and exhibit distinct phenotypic and functional features of M2 Mϕs. M2‐Exo has not only Mϕ reprogramming factors but also various cytokines and growth factors promoting wound repair. After subcutaneous administration of M2‐Exo into the wound edge, the local populations of M1 and M2 Mϕs are markedly decreased and increased, respectively, showing a successful exosome‐guided switch to M2 Mϕ polarization. The direct conversion of M1 to M2 Mϕs at the wound site accelerates wound healing by enhancing angiogenesis, re‐epithelialization, and collagen deposition. The Mϕ phenotype switching induced by exosomes possessing the excellent cell reprogramming capability and innate biocompatibility can be a promising therapeutic approach for various inflammation‐associated disorders by regulating the balance between pro‐ versus anti‐inflammatory Mϕs. [ABSTRACT FROM AUTHOR]

In the past few years, there have been many efforts underway to develop effective wound healing treatments for traumatic injuries. In particular, wound‐healing peptides (WHPs) and peptide‐grafted dressings hold great promise for novel therapeutic strategies for wound management. This study reports a topical formulation of a new synthetic WHP (REGRT, REG) embedded in a hyaluronic acid (HA)‐based hydrogel dressing for the enhancement of acute excisional wound repair. The copper‐free click chemistry is utilized to form biocompatible HA hydrogels by cross‐linking dibenzocyclooctyl‐functionalized HA with 4‐arm poly(ethylene glycol) (PEG) azide. The HA hydrogels are grafted with the REG peptide, a functional derivative of erythroid differentiation regulator1, displaying potent cell motility‐stimulating ability, thus sustainably releasing physiologically active peptides for a prolonged period. Combined with the traditional wound healing benefits of HA, the HA hydrogel embedded REG (REG‐HAgel) accelerates re‐epithelialization in skin wound healing, particularly by promoting migration of fibroblasts, keratinocytes, and endothelial cells. REG‐HAgels improve not only rate, but quality of wound healing with higher collagen deposition and more microvascular formation while being nontoxic. The peptide‐grafted HA hydrogel system can be considered as a promising new wound dressing formulation strategy for the treatment of different types of wounds with combinations of various natural and synthetic WHPs. A novel synthetic wound healing peptide (REGRT)‐grafted biocompatible hyaluronic acid hydrogel (HAgel) is introduced as a potential wound care strategy for the enhancement of acute excisional wound repair. As an advanced wound dressing platform, the bioactive REGRT and the HAgels cross‐linked via copper‐free click chemistry can have a synergistic effect in wound management. [ABSTRACT FROM AUTHOR]

On page 5518, an ultralong‐acting, liver‐specific, ultrasound contrast agent is presented in the form of self‐assembled, echogenic hyaluronic acid nanoparticles. I. C. Kwon, K. Kim, and co‐workers use hydrophobic interactions and an oilin‐water emulsification method to encapsulate bioinert and hydrophobic perfluoropentane as an ultrasound gas precursor into the nanoparticles. These particles are more stable and robust echogenic solid bodies than the conventional microbubbles, with an in vivo favorable hydrodynamic size. [ABSTRACT FROM AUTHOR]

A polyelectrolyte complex micelle (PECM)-based delivery system for targeting folate (FOL) receptor overexpressing tumor cells is demonstrated using poly(ethylene glycol) (PEG)-conjugated oligonucleotide (ODN). The tumor targeting property was conferred to the PECM by tethering a folate moiety to the distal end of the PEG segment in an anti-sense green fluorescent protein (GFP) ODN-PEG conjugate. Nanoscale PECMs were spontaneously produced from ionic interactions between the ODN-PEG-FOL conjugate and a cationic lipid, lipofectamine (Lf). When treated with FOL receptor overexpressing cells (KB), the PCEMs caused a significant reduction in GFP expression in a dose-dependent manner. This effect was not observed in FOL receptor deficient cells (A549). The enhanced transfection of ODN-PEG-FOL/Lf PECMs to KB cells was caused by FOL receptor mediated endocytosis. The efficiency of target-specific gene suppression by ODN-PEG-FOL/Lf PECMs was maintained even in the presence of 10% fetal bovine serum in the transfection medium.