Multifunctional nanoplatforms combined with photodynamic therapy (PDT) and anticancer drugs have shown great promising in cancer therapy. However, their efficacy is limited by the low specificity, ...low oxygen levels, and a tolerant tumor immune microenvironment. Herein, we developed a biocompatible theranostic nanoplatform (FM@VP) based on co-assembly of a nanocomplex formed by a functional polysaccharide fucoidan and a bioreducible polyamidoamine (PAMAM) dendrimer, a photosensitizer verteporfin (VP), and MnO2 nanoparticles (a tumor microenvironment responsive oxygen evolving nanomaterial) into a multifunctional nanoparticle cluster. The dendrimer-fucoidan polyionic nanocomplex (DFPN) specifically targeted P-selectin-overexpressed triple-negative breast cancer (TNBC) and the tumor-associated vasculature, and was sensitive to glutathione (GSH) in tumor. More importantly, this FM@VP nanocomplex simultaneously overcame tumor hypoxia, suppressed oncogenic signaling, and attenuated tumor-mediated immunosuppression, resulting in improving therapeutic efficacy of PDT while enhancing antitumor immunity and anti-metastasis. This discovery provides a powerful strategy for synergetic cancer targeting/photodynamic/immunotherapy and could serve as a safe clinical translational approach.
This study was to clarify the connection between extrinsic factors and the risk of perioperative pressure injuries (PIs) through the case–control approach, which involved making the intrinsic factors ...of the patients in the control group with no PIs consistent with those of the case group with PIs. We collected samples from a teaching hospital in Taiwan. We found a total of 132 patients deemed to have developed perioperative PIs. Using 1:2 frequency matching, we matched these cases with patients who had not developed PIs by gender, age, and BMI. Binary logistic regression analysis of the odds ratios of the extrinsic factors and PI risk revealed that the independent variables with statistical significance included duration of anaesthesia 3 h, amount of blood loss, use of electric blankets, diastolic blood pressure below 60 mmHg during surgery, and oxyhemoglobin saturation by pulse oximetry (SPO2) below 93% during surgery. Emphasis should be placed on cooperation among the medical team during surgery, less use of electric blankets, control over the duration of anaesthesia and blood loss, continuous monitoring of the patient during surgery for any emergencies, and the maintenance of patient diastolic blood pressure and blood oxygen levels to reduce the risk of PIs.
Nanostructure-based sensors are capable of sensitive and label-free detection for biomedical applications. However, plasmonic sensors capable of highly sensitive detection with high-throughput and ...low-cost fabrication techniques are desirable. We show that capped gold nanoslit arrays made by thermal-embossing nanoimprint method on a polymer film can produce extremely sharp asymmetric resonances for a transverse magnetic-polarized wave. An ultrasmall linewidth is formed due to the enhanced Fano coupling between the cavity resonance mode in nanoslits and surface plasmon resonance mode on periodic metallic surface. With an optimal slit length and width, the full width at half-maximum bandwidth of the Fano mode is only 3.68 nm. The wavelength sensitivity is 926 nm/RIU for 60-nm-width and 1,000-nm-period nanoslits. The figure of merit is up to 252. The obtained value is higher than the theoretically estimated upper limits of the prism-coupling SPR sensors and the previously reported record high figure-of-merit in array sensors. In addition, the structure has an ultrahigh intensity sensitivity up to 48,117%/RIU.
Osteoarthritis (OA) is a common articular disease manifested by the destruction of cartilage and compromised chondrogenesis in the aging population, with chronic inflammation of synovium, which ...drives OA progression. Importantly, the activated synovial fibroblast (AF) within the synovium facilitates OA through modulating key molecules, including regulatory microRNAs (miR's). To understand OA associated pathways, in vitro co-culture system, and in vivo papain-induced OA model were applied for this study. The expression of key inflammatory markers both in tissue and blood plasma were examined by qRT-PCR, western blot, immunohistochemistry, enzyme-linked immunosorbent assay (ELISA) and immunofluorescence assays. Herein, our result demonstrated, AF-activated human chondrocytes (AC) exhibit elevated NFκB, TNF-α, IL-6, and miR-21 expression as compared to healthy chondrocytes (HC). Importantly, AC induced the apoptosis of HC and inhibited the expression of chondrogenesis inducers, SOX5, TGF-β1, and GDF-5. NFκB is a key inflammatory transcription factor elevated in OA. Therefore, SC75741 (an NFκB inhibitor) therapeutic effect was explored. SC75741 inhibits inflammatory profile, protects AC-educated HC from apoptosis, and inhibits miR-21 expression, which results in the induced expression of GDF-5, SOX5, TGF-β1, BMPR2, and COL4A1. Moreover, ectopic miR-21 expression in fibroblast-like activated chondrocytes promoted osteoblast-mediated differentiation of osteoclasts in RW264.7 cells. Interestingly, in vivo study demonstrated SC75741 protective role, in controlling the destruction of the articular joint, through NFκB, TNF-α, IL-6, and miR-21 inhibition, and inducing GDF-5, SOX5, TGF-β1, BMPR2, and COL4A1 expression. Our study demonstrated the role of NFκB/miR-21 axis in OA progression, and SC75741's therapeutic potential as a small-molecule inhibitor of miR-21/NFκB-driven OA progression.
In this review article, we explore the characteristics of RNA viruses and their potential threats to humanity. We also provide a brief overview of the primary contemporary techniques used for the ...early detection of such viruses. After thoroughly analyzing the strengths and limitations of these methods, we highlight the importance of integrating nucleic acid testing with immunological assays in RNA virus detection. Although notable methodological differences between nucleic acid testing and immune assays pose challenges, the emerging single-molecule immunoassay-digital ELISA may be applied to technically integrate these techniques. We emphasize that the greatest value of digital ELISA is its extensive compatibility, which creates numerous opportunities for real-time, large-scale testing of RNA viruses. Furthermore, we describe the possible developmental trends of digital ELISA in various aspects, such as reaction carriers, identification elements, signal amplification, and data reading, thus revealing the remarkable potential of single-molecule digital ELISA in future RNA virus detection.
Osteoarthritis (OA) is most prevalent in older individuals and exerts a heavy social and economic burden. However, an effective and noninvasive approach to OA treatment is currently not available. ...Chondrocyte senescence has recently been proposed as a key pathogenic mechanism in the etiology of OA. Furthermore, senescent chondrocytes (SnCCs) can release various proinflammatory cytokines, proteolytic enzymes, and other substances known as the senescence-associated secretory phenotype (SASP), allowing them to connect with surrounding cells and induce senesce. Studies have shown that the pharmacological elimination of SnCCs slows the progression of OA and promotes regeneration. Growth differentiation factor 15 (GDF15), a member of the tumor growth factor (TGF) superfamily, has recently been identified as a possible aging biomarker and has been linked to a variety of clinical conditions, including coronary artery disease, diabetes, and multiple cancer types. Thus, we obtained data from a publicly available single-cell sequencing RNA database and observed that GDF15, a critical protein in cellular senescence, is highly expressed in early OA. In addition, GDF15 is implicated in the senescence and modulation of MAPK14 in OA. Tissue and synovial fluid samples obtained from OA patients showed overexpression of GDF15. Next, we treated C20A4 cell lines with interleukin (IL)-1β with or without shGDF15 then removed the conditioned medium, and cultured C20A4 and HUVEC cell lines with the aforementioned media. We observed that C20A4 cells treated with IL-1β exhibited increased GDF15 secretion and that chondrocytes cultured with media derived from IL-1β–treated C20A4 exhibited senescence. HUVEC cell migration and tube formation were enhanced after culturing with IL-1β-treated chondrocyte media; however, decreased HUVEC cell migration and tube formation were noted in HUVEC cells cultured with GDF15-loss media. We tested the potential of inhibiting GDF15 by using a GDF15 neutralizing antibody, GDF15-nAb. GDF15-nAb exerted a similar effect, resulting in the molecular silencing of GDF15 in vivo and in vitro. Our results reveal that GDF15 is a driver of SnCCs and can contribute to OA progression by inducing angiogenesis.
Double-hit lymphoma (DHL) is an aggressive subset of Diffuse Large B-cell Lymphoma (DLBCL) with poor outcomes and without satisfying treatment options. BTK inhibitor monotherapy is ineffective to ...suppress aggressive lymphoma. Hence, combination with other potential agents is warranted. Here, we demonstrated the second generation of BTK inhibitor, zanubrutinib, and a BCL-2 inhibitor, navitoclax, worked in synergistic manner to suppress DHL. Comprehensive in silico approach by interrogating single-cell to bulk-level profiling was employed along with in vitro and in vivo validation in DHL cell lines. Ablation of BTK enhanced sensitivity to navitoclax and suppressed proliferation of DHL cells. Combination of second generation of BTK inhibitor with navitoclax synergistically suppressed DLBCL cells with higher synergy score in DHL subset. The drug combination triggered apoptosis and ferroptosis, with the latter being characterized by reactive oxygen species (ROS) accumulation, extensive lipid peroxidation, and depletion of reduced glutathione. Moreover, ablation of BTK sensitized DHL cells to ferroptosis. Mechanistically, disruption of BTK and BCL-2 triggered ferroptosis by downregulating NRF2 and HMOX1, while deactivating GPX4. Combination of zanubrutinib and navitoclax effectively suppressed tumor growth in vivo. Our data suggest that zanubrutinib and navitoclax synergistically suppressed DHL by inducing apoptosis and ferroptosis.
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•Bruton's Tyrosine Kinase (BTK) maintained survival of Double-Hit Lymphoma (DHL).•Ablation of BTK Increased Sensitivity to BCL-2 Inhibition.•Disruption of BTK Enhanced Ferroptosis Sensitivity of DHL.•Inhibitor of BTK and BCL-2 Synergistically Suppressed DHL.•Zanubrutinib and Navitoclax Triggers Apoptosis and Ferroptosis in DHL.
Understanding the endocytosis process of gold nanoparticles (AuNPs) is important for the drug delivery and photodynamic therapy applications. The endocytosis in living cells is usually studied by ...fluorescent microscopy. The fluorescent labeling suffers from photobleaching. Besides, quantitative estimation of the cellular uptake is not easy. In this paper, the size-dependent endocytosis of AuNPs was investigated by using plasmonic scattering images without any labeling.
The scattering images of AuNPs and the vesicles were mapped by using an optical sectioning microscopy with dark-field illumination. AuNPs have large optical scatterings at 550-600 nm wavelengths due to localized surface plasmon resonances. Using an enhanced contrast between yellow and blue CCD images, AuNPs can be well distinguished from cellular organelles. The tracking of AuNPs coated with aptamers for surface mucin glycoprotein shows that AuNPs attached to extracellular matrix and moved towards center of the cell. Most 75-nm-AuNPs moved to the top of cells, while many 45-nm-AuNPs entered cells through endocytosis and accumulated in endocytic vesicles. The amounts of cellular uptake decreased with the increase of particle size.
We quantitatively studied the endocytosis of AuNPs with different sizes in various cancer cells. The plasmonic scattering images confirm the size-dependent endocytosis of AuNPs. The 45-nm-AuNP is better for drug delivery due to its higher uptake rate. On the other hand, large AuNPs are immobilized on the cell membrane. They can be used to reconstruct the cell morphology.
•The relationship among the users, helpers and server, is modeled as a cooperative protection system architecture.•Community structure based trilateral Stackelberg game model is proposed for ...achieving the collaboration ability.•The optimization method based on proposed model is designed by the backward induction process.•The security and the performances of proposed model and method are analyzed under different situations.
Location-based services are widely used in mobile applications, which not only bring convenience, but also cause serious privacy concerns. Based on the characteristics of social network, this work proposes a cooperative protection architecture to model the relationship among users, communities and location-based service. Furthermore, in order to construct K anonymity set, a novel community structure-based trilateral Stackelberg game model is developed for K-anonymity protection. In addition, an optimization method based on the proposed model is designed by the backward induction process. Finally, the security and the performance under different situations such as the anonymity parameter K and the community structure parameter overlapping weights are analyzed. The analysis results indicate that the proposed model and the optimization method are effective for privacy protection and can achieve high secure in location-based services.
To integrate massive amounts of heterogeneous biomedical data in biomedical ontologies and to provide more options for clinical diagnosis, this work proposes an adaptive Multi-modal Multi-Objective ...Evolutionary Algorithm (aMMOEA) to match two heterogeneous biomedical ontologies by finding the semantically identical concepts. In particular, we first propose two evaluation metrics on the alignment's quality, which calculate the alignment's statistical and its logical features, i.e., its f-measure and its conservativity. On this basis, we build a novel multi-objective optimization model for the biomedical ontology matching problem. By analyzing the essence of this problem, we point out that it is a large-scale Multi-modal Multi-objective Optimization Problem (MMOP) with sparse Pareto optimal solutions. Then, we propose a problem-specific aMMOEA to solve this problem, which uses the Guiding Matrix (GM) to adaptively guide the algorithm's convergence and diversity in both objective and decision spaces. The experiment uses Ontology Alignment Evaluation Initiative (OAEI)'s biomedical tracks to test aMMOEA's performance, and comparisons with two state-of-the-art MOEA-based matching techniques and OAEI's participants show that aMMOEA is able to effectively determine diverse solutions for decision makers.
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