Graphene oxide has unique physiochemical properties, showing great potential in biomedical applications. In the present work, functionalized reduced graphene oxide (PEG-BPEI-rGO) has been developed ...as a nanotemplate for photothermally triggered cytosolic drug delivery by inducing endosomal disruption and subsequent drug release. PEG-BPEI-rGO has the ability to load a greater amount of doxorubicin (DOX) than unreduced PEG-BPEI-GO via π–π and hydrophobic interactions, showing high water stability. Loaded DOX could be efficiently released by glutathione (GSH) and the photothermal effect of irradiated near IR (NIR) in test tubes as well as in cells. Importantly, PEG-BPEI-rGO/DOX complex was found to escape from endosomes after cellular uptake by photothermally induced endosomal disruption and the proton sponge effect, followed by GSH-induced DOX release into the cytosol. Finally, it was concluded that a greater cancer cell death efficacy was observed in PEG-BPEI-rGO/DOX complex-treated cells with NIR irradiation than those with no irradiation. This study demonstrated the development of the potential of a PEG-BPEI-rGO nanocarrier by photothermally triggered cytosolic drug delivery via endosomal disruption.
Achieving a deep molecular response (DMR) to tyrosine kinase inhibitor (TKI) therapy for chronic myeloid leukemia (CML) remains challenging and at present, there is no biomarker to predict DMR in ...this setting. Herein, we report that an HMGCLL1 genetic variant located in 6p12.1 can be used as a predictive genetic biomarker for intrinsic sensitivity to imatinib (IM) therapy. We measured DMR rate according to HMGCLL1 variant in a discovery set of CML patients (n = 201) and successfully replicated it in a validation set (n = 270). We also investigated the functional relevance of HMGCLL1 blockade with respect to response to TKI therapy and showed that small interfering RNA mediated blockade of HMGCLL1 isoform 3 results in significant decrease in viability of BCR-ABL1-positive cells including K562, CML-T1 or BaF3 cell lines with or without ABL1 kinase domain mutations such as T315I mutation. Decreased cell viability was also demonstrated in murine CML stem cells and human hematopoietic progenitor cells. RNA sequencing showed that blockade of HMGCLL1 was associated with G0/G1 arrest and the cell cycle. In summary, the HMGCLL1 gene polymorphism is a novel genetic biomarker for intrinsic sensitivity to IM therapy in CML patients that predicts DMR in this setting.
Liver fibrosis is a wound healing process that includes inflammation, deposition of extracellular matrix molecules, and pathological neovascularization. Angiogenesis, which is defined by the ...formation of new blood vessels from pre-existing vessels, is a complex and dynamic process under both physiological and pathological conditions. Although whether angiogenesis can induce or occur in parallel with the progression of hepatic fibrosis has not yet been determined, intrahepatic sinusoidal formation and remodeling are key features of liver fibrosis. Some recent evidence has suggested that experimental inhibition of angiogenesis ameliorates the development of liver fibrosis, while other recent studies indicate that neutralization or genetic ablation of vascular endothelial growth factor (VEGF) in myeloid cells can delay tissue repair and fibrosis resolution in damaged liver. In this review, we briefly summarize the current knowledge about the differential roles of angiogenesis in the induction of fibrogenesis and the resolution of fibrosis in damaged livers. Possible strategies for the prevention and treatment of liver fibrosis are also discussed.
Given the increasing evidence indicates that many pathological conditions are associated with elevated reactive oxygen species (ROS) levels, there have been growing research efforts focused on the ...development of ROS‐responsive carrier systems because of their promising potential to realize more specific diagnosis and effective therapy. By judicious utilization of ROS‐responsive functional moieties, a wide range of carrier systems has been designed for ROS‐mediated drug delivery. In this review article, insights into design principle and recent advances on the development of ROS‐responsive carrier systems for drug delivery applications are provided alongside discussion of their in vitro and in vivo evaluation. In particular, the discussions in this article will mainly focus on polymeric nanoparticles, hydrogels, inorganic nanoparticles, and activatable prodrugs that have been integrated with diverse ROS‐responsive moieties for spatiotemporally controlled release of drugs for effective therapy.
Based on reactive‐oxygen‐species (ROS)‐responsive materials, design principle and recent advances on the ROS‐responsive carrier systems for drug delivery systems including polymeric nanoparticles, hydrogels, inorganic nanoparticles, and activatable prodrugs are reviewed.
Background: Left atrial appendage occlusion (LAAO) plays an important role in preventing stroke in patients with atrial fibrillation. However, LAAO may interact unfavorably with left atrial (LA) ...compliance and reservoir function and thus increase the risk of heart failure (HF). The purpose of this study was to identify predictors of subsequent HF after successful LAAO.Methods and Results: A total of 98 patients (mean age 70±9 years, 68% male) who had undergone LAAO were included. The primary endpoint was unexpected HF admission after LAAO. During a mean period of 36±26 months, 16 of the 98 patients (16%) experienced hospital HF admission. In multivariate analysis, higher E/e’ (hazard ratio HR 1.11, 95% confidence interval CI 1.02–1.20, P=0.014), higher left ventricular mass index (HR 1.02, 95% CI 1.00–1.03, P=0.023), history of HF (HR 4.78, 95% CI 1.55–14.7, P=0.006), and lower LA strain (HR 0.80, 95% CI 0.70–0.93, P=0.003) were independently associated with hospital HF admission. Patients with LAAO had a significantly higher incidence of subsequent HF than the control group after propensity score matching (P=0.046).Conclusions: LAAO increases the occurrence of HF, and it is not uncommon after successful LAAO. A previous history of HF, left ventricular mass index, E/e’, and abnormal LA strain are independently associated with the development of HF. These parameters should be considered before attempting LAAO.
Current hyaluronic acid (HA) hydrogel systems often cause cytotoxicity to encapsulated cells and lack the adhesive property required for effective localization of transplanted cells in vivo. In ...addition, the injection of hydrogel into certain organs (e.g., liver, heart) induces tissue damage and hemorrhage. In this study, we describe a bioinspired, tissue‐adhesive hydrogel that overcomes the limitations of current HA hydrogels through its improved biocompatibility and potential for minimally invasive cell transplantation. HA functionalized with an adhesive catecholamine motif of mussel foot protein forms HA‐catechol (HA‐CA) hydrogel via oxidative crosslinking. HA‐CA hydrogel increases viability, reduces apoptosis, and enhances the function of two types of cells (human adipose‐derived stem cells and hepatocytes) compared with a typical HA hydrogel crosslinked by photopolymerization. Due to the strong tissue adhesiveness of the HA‐CA hydrogel, cells are easily and efficiently transplanted onto various tissues (e.g., liver and heart) without the need for injection. Stem cell therapy using the HA‐CA hydrogel increases angiogenesis in vivo, leading to improved treatment of ischemic diseases. HA‐CA hydrogel also improved hepatic functions of transplanted hepatocytes in vivo. Thus, this bioinspired, tissue‐adhesive HA hydrogel can enhance the efficacy of minimally invasive cell therapy.
Bioinspired, catechol‐modified hyaluronic acid (HA) hydrogel is highly biocompatible and exhibits improved tissue adhesiveness in comparison to HA hydrogel crosslinked via photopolymerization. Tissue adhesive catechol‐modified HA hydrogel can mediate highly effective, minimally invasive cell therapy in defected models such as liver resection and myocardial infarction.
The uncontrollable dendritic growth of metallic lithium during repeated cycling in carbonate electrolytes is a crucial obstacle hindering the practical use of Li‐metal batteries (LMBs). Among ...numerous approaches proposed to mitigate the intrinsic constraints of Li metal, the design of a functional separator is an attractive approach to effectively suppress the growth of Li dendrites because direct contact with both the Li metal surface and the electrolyte is maintained. Here, a newly designed all‐in‐one separator containing bifunctional CaCO3 nanoparticles (CPP separator) is proposed to achieve the flattening of Li deposits on the Li electrode. Strong interactions between the highly polar CaCO3 nanoparticles and the polar solvent reduces the ionic radius of the Li+‐solvent complex, thus increasing the Li+ transference number and leading to a reduced concentration overpotential in the electrolyte‐filled separator. Furthermore, the integration of CaCO3 nanoparticles into the separator induces the spontaneous formation of mechanically‐strong and lithiophilic CaLi2 at the Li/separator interface, which effectively decreases the nucleation overpotential toward Li plating. As a result, the Li deposits exhibit dendrite‐free planar morphologies, thus enabling excellent cycling performance in LMBs configured with a high‐Ni cathode in a carbonate electrolyte under practical operating conditions.
CPP separator is developed. The one‐body structure minimizes the sacrifice in energy density even with the inorganic particle introduction. Polar CaCO3 alters the solvation structure of Li+, enhancing Li+ mobility and reducing concentration overpotential. Concurrently, CaCO3 reacts with Li to form lithiophilic CaLi alloy spontaneously, reducing the nucleation overpotential. Because of the overall overpotential control, dendrite‐free Li deposition is achieved.
Background and Aims
Studies on differential effect of aspirin therapy on HCC risk across the spectrum of liver diseases are lacking. We investigated the association between aspirin use and risks of ...HCC, liver‐associated death, and major bleeding in chronic hepatitis B (CHB) patients with or without cirrhosis.
Approach and Results
We identified 329,635 eligible adults with CHB from 2007 through 2017, using the Korean National Health Insurance Service database, including patients who received aspirin for ≥90 consecutive days (n = 20,200) and patients who never received antiplatelet therapy (n = 309,435). Risks of HCC, liver‐associated mortality, and major bleeding were estimated in a propensity‐score–matched cohort (19,003 pairs), accounting for competing risks. With a median follow‐up of 6.7 years, 10‐year cumulative incidence of HCC was 9.5% in the aspirin‐treated group and 11.3% in the untreated group (adjusted subdistribution hazard ratio aSHR, 0.85; 95% CI, 0.78–0.92). However, among patients with cirrhosis (2479 pairs), an association of aspirin use with HCC risk was not evident (aSHR, 1.00; 95% CI, 0.85–1.18). Cirrhosis status had a significant effect on the association between aspirin use and HCC risk (pinteraction, n = 0.04). Aspirin use was also associated with lower liver‐associated mortality (aSHR, 0.80; 95% CI, 0.71–0.90). Moreover, aspirin use was not associated with major bleeding risk (aSHR, 1.09; 95% CI, 0.99–1.21).
Conclusions
Aspirin use was associated with reduced risks of HCC and liver‐associated mortality in adults with CHB. Cirrhosis status had a substantial effect on the association between aspirin use and HCC risk.
Abstract
The realisation of fast-charging lithium-ion batteries with long cycle lifetimes is hindered by the uncontrollable plating of metallic Li on the graphite anode during high-rate charging. ...Here we report that surface engineering of graphite with a cooperative biphasic MoO
x
–MoP
x
promoter improves the charging rate and suppresses Li plating without compromising energy density. We design and synthesise MoO
x
–MoP
x
/graphite via controllable and scalable surface engineering, i.e., the deposition of a MoO
x
nanolayer on the graphite surface, followed by vapour-induced partial phase transformation of MoO
x
to MoP
x
. A variety of analytical studies combined with thermodynamic calculations demonstrate that MoO
x
effectively mitigates the formation of resistive films on the graphite surface, while MoP
x
hosts Li
+
at relatively high potentials via a fast intercalation reaction and plays a dominant role in lowering the Li
+
adsorption energy. The MoO
x
–MoP
x
/graphite anode exhibits a fast-charging capability (<10 min charging for 80% of the capacity) and stable cycling performance without any signs of Li plating over 300 cycles when coupled with a LiNi
0.6
Co
0.2
Mn
0.2
O
2
cathode. Thus, the developed approach paves the way to the design of advanced anode materials for fast-charging Li-ion batteries.
Stretchable semiconducting polymers have been developed as a key component to enable skin-like wearable electronics, but their electrical performance must be improved to enable more advanced ...functionalities. Here, we report a solution processing approach that can achieve multi-scale ordering and alignment of conjugated polymers in stretchable semiconductors to substantially improve their charge carrier mobility. Using solution shearing with a patterned microtrench coating blade, macroscale alignment of conjugated-polymer nanostructures was achieved along the charge transport direction. In conjunction, the nanoscale spatial confinement aligns chain conformation and promotes short-range π-π ordering, substantially reducing the energetic barrier for charge carrier transport. As a result, the mobilities of stretchable conjugated-polymer films have been enhanced up to threefold and maintained under a strain up to 100%. This method may also serve as the basis for large-area manufacturing of stretchable semiconducting films, as demonstrated by the roll-to-roll coating of metre-scale films.
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