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The cluster of differentiation 47 (CD47) protein is abundantly expressed on various malignant cells and suppresses the phagocytic function of macrophages and dendritic cells. High CD47 expression levels are correlated with poor cancer survival. Antagonizing CD47 antibodies with potent antitumor effects have been developed in clinical trials, but have critical side effects, inducing anemia and thrombocytopenia. To develop a safe and potent CD47 blockade, we designed extracellular vesicles (EVs) harboring signal regulatory protein alpha (SIPRα)-EV-SIRPα (EVs that express SIPRα). EV-SIRPα showed minimal toxic effects on hematologic parameters and utilized RBCs as delivery vehicles to tumors rather than inducing anemia. EV-SIRPα inhibited ligation of residual CD47 molecules, which attribute to the EV-endocytosis-mediated CD47 depletion and steric hindrance of EV. In an immunologically cold tumor model, EV-SIRPα induced tumor-specific T-cell-mediated antitumor effects. When directly administered to the accessible lesions, EV-SIRPα monotherapy elicited an abscopal effect in the B16F10 tumor model by increasing immune cell infiltration and CD8sup+/sup-mediated immunity against non-treated tumors. The combinational approach by loading doxorubicin into the EV-SIRPα dramatically reduced the tumor burden and led to 80% complete remission rate. Thus, a potent EV-based CD47 blockade that is hematologically safe, has efficient signaling blocking efficacy, and has systemic antitumor immunity against cancer is recommended.

Plasmonic nanoantennas have been extensively explored to boost nonlinear optical processes due to their capabilities to confine optical fields on the nanoscale. In harmonic generation, nanoantenna array architectures are often employed to increase the number of emitters in order to efficiently enhance the harmonic emission. A small laser focus spot on the nanoantenna array maximizes the harmonic yield since it scales nonlinearly with the incident laser intensity. However, the nonlinear yield of the nanoantennas lying at the boundary of a focused beam may exhibit significant deviations in comparison to those at the center of the beam due to the Gaussian intensity distribution of the beam. This spatial beam inhomogeneity can cause power instability of the emitted harmonics when the lateral beam position is not stable which we observed in plasmon-enhanced third-harmonic generation (THG). Hence, we propose a method for deterministically designing the density of a nanoantenna array to decrease the instability of the beam position-dependent THG yield. This method is based on reducing the ratio between the number of ambiguous nanoantennas located at the beam boundary and the total number of nanoantennas within the beam diameter to increase the plasmon-enhanced THG stability, which we term as the ratio of ambiguity (ROA). We find that the coefficient of variation of the measured plasmonic THG yield enhancement decreases with the ROA. Thus, our method is beneficial for designing reliable sensors or nonlinear optical devices consisting of nanoantenna arrays for enhancing output signals.

The ferritin nanocage is an endogenous protein that exists in almost all mammals. Its hollow spherical structure that naturally stores iron ions has been diversely exploited by researchers in biotherapeutics. Ferritin has excellent biosafety profiles, and the nanosized particles exhibit rapid dispersion and controlled/sustained release pharmacokinetics. Moreover, the large surface-to-volume ratio and the disassembly/reassembly behavior of the 24 monomer subunits into a sphere allow diverse modifications by chemical and genetic methods on the surface and inner cage of ferritin. Here, we critically review ferritin and its applications. We (i) introduce the application of ferritin in drug delivery; (ii) present an overview of the use of ferritin in imaging and diagnosis for biomedical purposes; (iii) discuss ferritin-based vaccines; and (iv) review ferritin-based agents currently in clinical trials. Although there are no currently approved drugs based on ferritin, this multifunctional protein scaffold shows immense potential in drug development in diverse categories, and ferritin-based drugs have recently entered phase I clinical trials. This golden shortlist of recent developments will be of immediate benefit and interest to researchers studying ferritin and other protein-based biotherapeutics.

Recently, the λ-analogues of r-Stirling numbers of the first kind were studied by Kim-Kim. The aim of this paper is to introduce the λ-analogues of r-Stirling numbers of the second kind and to investigate some properties, recurrence relations and certain identities on those numbers. We also introduce the λ-analogues of Whitney-type r-Stirling numbers of the second and derive similar results to the case of the λ-analogues of r-Stirling numbers of the second kind. In addition, we consider the λ-analogues of Dowling polynomials and deduce a Dobinski-like formula.

Koreanohadra koreana (K. koreana) is an endemic species in South Korea that is listed as endangered. While the ecology and phylogenetics of K. koreana have been studied, its morphological similarity to the related species Koreanohadra kurodana (K. kurodana), can make species identification difficult. Furthermore, this has led to confusion when determining essential habitat information for the conservation of K. koreana. To bypass this issue, we have developed a noninvasive species identification method that can genetically differentiate between them. While there are already various noninvasive genomic DNA (gDNA) extraction methods that utilize the mucus from mollusks, they are limited as they require the target species to be physically located. To address this, in this investigation a method of extracting gDNA from the feces of snails was developed. The method utilized a primer set to amplify a cytochrome b fragment from K. koreana but not K. kurodana or other terrestrial snails. The feces of terrestrial snails could thus be used to obtain gDNA to a genetically usable level if collected within 5 days of excretion. This noninvasive species identification method using feces will help to facilitate genetic research without harming the endangered species and if the target species is not physically in the habitat. Moreover, K. koreana and K. kurodana could perhaps be further distinguished, using their habitat information to help facilitate essential conservation measures.

Background This study aimed to evaluate the cost utility of pharmacopuncture in comparison with usual care for patients with chronic neck pain.Methods A 12-week, multicenter, pragmatic randomized controlled trial was conducted, and 101 patients suffering from chronic neck pain for more than six months were randomly placed into the pharmacopuncture and usual care groups to receive four weeks of treatment and 12 weeks of follow-up observations. The quality-adjusted life year (QALY) was calculated using EQ-5D and SF-6D. Concerning costs in 2019, a primary analysis was performed on societal perspective cost, and an additional analysis was performed on healthcare perspective cost.Results Compared to usual care, pharmacopuncture was superior as it showed a slightly higher QALY and a lower incremental cost of $1,157 from a societal perspective. The probability that pharmacopuncture would be more cost-effective at a willingness-to-pay (WTP) of $26,374 was 100%. Pharmacopuncture was also superior from a healthcare perspective, with a lower incremental cost of $26. The probability that pharmacopuncture would be more cost-effective at a WTP of $26,374 was 83.7%.Conclusions Overall, pharmacopuncture for chronic neck pain was found to be more cost-effective compared to usual care, implying that clinicians and policy makers should consider new treatment options for neck pain.

It is known that VEGF receptors (VEGFR) and integrins interact with each other to regulate angiogenesis. We reported previously that the fasciclin 1 (FAS1) domain–containing protein, TGFBIp/βig-h3 (TGF-β–induced protein) is an angiogenesis regulator that inhibits both endothelial cell migration and growth via αvβ3 integrin. In an attempt to target the interaction between VEGFR-2 and αvβ3 integrin, we determined whether the FAS1 domain region of TGFBIp/βig-h3 (FAS1 domain protein) can block the interaction between the two receptors, leading to the suppression of angiogenesis. In this study, we showed that FAS1 domain protein inhibits VEGF165-induced endothelial cell proliferation and migration via αvβ3 integrin, resulting in the inhibition of VEGF165-induced angiogenesis. We also defined a molecular mechanism by which FAS1 domain protein blocks the association between αvβ3 integrin and VEGFR-2, showing that it binds to αvβ3 integrin but not to VEGFR-2. Blocking the association of these major angiogenic receptors with FAS1 domain protein inhibits signaling pathways downstream of VEGFR-2. Collectively, our results indicate that FAS1 domain protein, in addition to its inhibitory effect on αvβ3 integrin–mediated angiogenesis, also inhibits VEGF165-induced angiogenesis. Thus, FAS1 domain protein can be further developed into a potent anticancer drug that targets two principal angiogenic pathways. Mol Cancer Res; 10(8); 1010–20. ©2012 AACR.

PDF file - 259K, S1 Cell cytotoxicity assay. S2 FAS1-domain protein inhibits VEGF165-induced 9 association of alphavbeta3 integrin with VEGFR-2 and VEGFR-2 phosphorylation via alphavbeta3 10 integrin. S3 FAS1-domain protein inhibits both vitronectin- and 32 collagen-i 1 nduced VEGFR-2 phosphorylation and association of alphavbeta3 integrin with 2 VEGFR-2. S4 Serum-starved VEGFR-2/beta5/HEK293 cells were plated on collagen I-coated in serum-free 16 medium supplemented with FAS1-domain protein (10 muM) for 30 min, followed by 17 stimulation for 5 min with VEGF165 (20 ng/ml) or vehicle alone

Supplementary Table S1 from Targeting Bladder Tumor Cells In vivo and in the Urine with a Peptide Identified by Phage Display

Bladder cancer is one of the most common tumors of the genitourinary tract. Here, we use phage display to identify a peptide that targets bladder tumor cells. A phage library containing random peptides was screened for binding to cells from human bladder tumor xenografts. Phage clones were further selected for binding to a bladder tumor cell line in culture. Six clones displaying the consensus sequence CXNXDXRX/RC showed selective binding to cells from primary human bladder cancer tissue. Of these, the CSNRDARRC sequence was selected for further study as a synthetic peptide. Fluorescein-conjugated CSNRDARRC peptide selectively bound to frozen sections of human bladder tumor tissue, whereas only negligible binding to normal bladder tissue was observed. When the fluorescent peptide was introduced into the bladder lumen, in a carcinogen-induced rat tumor model, it selectively bound to tumor epithelium. Moreover, when the peptide was intravenously injected into the tail vein, it homed to the bladder tumor but was not detectable in normal bladder and control organs. Next, we examined whether the peptide can detect tumor cells in urine. The fluorescent peptide bound to cultured bladder tumor cells but not to other types of tumor cell lines. Moreover, it bound to urinary cells of patients with bladder cancer, while showing little binding to urinary cells of patients with inflammation or healthy individuals. The CSNRDARRC peptide may be useful as a targeting moiety for selective delivery of therapeutics and as a diagnostic probe for the detection of bladder cancer. (Mol Cancer Res 2007;5(1):11–19)

The aim of this paper is to represent any polynomial in terms of degenerate Frobenius–Euler polynomials and, more generally, of higher-order degenerate Frobenius–Euler polynomials. Explicit formulas with the help of umbral calculus are derived and the obtained results are illustrated by some examples.

Despite the availability of clinical practice guidelines for temporomandibular disorders (TMDs), research evidence on current clinical practice trends is scarce.This study aimed to analyse the TMD treatment trends and patterns according to patient characteristics in Korea over a 9-year period.The 2010-2018 Korean Health Insurance ReviewAssessment Service National Patient Sample data were used. A total of 109 969 patients diagnosed with TMD as the principal diagnosis at least once in each year were included in the study. The types of visits and treatments were analysed by year. K-medoids clustering was then performed to analyse the treatment patterns according to patient characteristics.The most commonly used drugs for pharmacological treatment were non-steroidal anti-inflammatory drugs (NSAIDs) and relaxants. The prescription of opioids, anxiolytics and antidepressants was reduced. Among non-pharmacological treatments, physiotherapy was the most utilised, and its use increased over the years. Cluster analysis showed that treatment patterns generally differed between sexes; the rate of outpatient visits and the use of NSAIDs, relaxants and physiotherapy were higher among female patients.This study showed that TMD treatment prescriptions changed from 2010 to 2018 and found notable trends in NSAIDs, relaxants, opioids, anxiolytics, antidepressants and physiotherapy. Moreover, the treatment patterns differed between the sexes. These findings indicate that the prescriptions for TMD treatment changed over the years; these results may be useful in the development of future clinical guidelines and should be reflected in future guidelines.