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Abstract Minimizing drug leakage at off-target sites and triggering sufficient drug release in tumor tissue are major objectives for effective nanoparticle (NP)-based cancer therapy. The current covalent and cleavable drug-NP conjugation strategy is promising but lacks high controllability to realize tumor-specific release. As a proof-of-concept, the reactive oxygen species (ROS)-activatable thioketal (TK) bond was explored as the linkage between doxorubicin (DOX) and polyphosphoester (PPE- TK -DOX). The Ce6@PPE- TK -DOX NPs constructed by co-self-coassembly of PPE- TK -DOX and the photosensitizer Ce6 efficiently prevented premature drug leakage in the off-target tissue and cells because of the high stability of the TK bond under physiological conditions. Once circulating into the tumor site, the 660-nm red light was precisely employed to irradiate the tumor area under the guidance of fluorescence/magnetic resonance (MR) dual-model imaging, which can induce localized ROS generation, resulting in rapid cleavage of the TK bond. Consequently, the DOX prodrug was locoregionally released and activated, achieving tumor-specific drug delivery with high controllability by light. Such phototriggered prodrug release and activation at the desired site significantly enhanced the therapeutic efficacy and minimized the side effect, providing new avenues to develop drug delivery systems for remote on-demand drug delivery in vivo. Graphical abstract Image 1 [ABSTRACT FROM AUTHOR]

Controlling poly(ethylene glycol) (PEG) shielding/deshielding at the desired site of action exhibits great advantages for nanocarrier-based on-demand drug delivery in vivo . However, the current PEG deshielding strategies were mainly designed for anticancer drug delivery; even so, their applications are also limited by tumor heterogeneity. As a proof-of-concept, we explored a photoinduced PEG deshielding nanocarrier TK-NP Ce6&PTX to circumvent the aforementioned challenge. The TK-NP Ce6&PTX encapsulating chlorin e6 (Ce6) and paclitaxel (PTX) was self-assembled from an innovative thioketal (TK) linkage-bridged diblock copolymer of PEG with poly(d, l -lactic acid) (PEG- TK -PLA). We demonstrated that the high PEGylation of TK-NP Ce6&PTX in blood helps the nanocarrier efficiently avoid rapid clearance and consequently prolongs its circulation time. At the desired site (tumor), 660-nm red light irradiation led to ROS generation in situ , which readily cleaved the TK linkage, resulting in PEG deshielding. Such photoinduced PEG deshielding at the desired site significantly enhances the cellular uptake of the nanocarriers, achieving on-demand drug delivery and superior therapeutic efficacy. More importantly, this strategy of photoinducing PEG deshielding of nanocarriers could potentially extend to a variety of therapeutic agents beyond anticancer drugs for on-demand delivery. [ABSTRACT FROM AUTHOR]

In this paper, a novel nested photonic crystal fiber (PCF) with two guided modes regions is proposed, which can support 80 orbital angular momentum (OAM) modes over C wavelength band. The characteristics of designed nested PCF are systematically analyzed by using the finite element method (FEM). The results show that the isolation is kept above 40dB, the crosstalk between different guided modes regions can be neglected, and the dispersion is relatively flat, the nonlinear coefficient is lower than 2.65km−1W−1. Additionally, the confinement loss and effective mode field area of the designed nested PCF are also analyzed. In summary, the designed nested PCF has potential applications in the high capacity fiber communication of mode division multiplexing (MDM). [ABSTRACT FROM AUTHOR]

A squeezed triangular lattice photonic crystal fiber (PCF) composed of elliptical air holes is presented in this paper. Full vector finite element method (FEM) is used to investigate the guiding property. By adjusting the size of air holes in cladding, the fiber offers a flat negative dispersion of -1343.46 ± 6.74 ps/(nm.km) over the wavelength bands of S+C+L+U. The birefringence can be on the order of 1 0 − 2 which reaches up to 3.72 × 1 0 − 2 at the wavelength of 1. 55 μ m. The proposed PCF may show some important applications in residual dispersion compensation and polarization maintaining fibers. [ABSTRACT FROM AUTHOR]

Tumors with a low level of pre-existing immune cell infiltration respond poorly to immune checkpoint therapies. Oncolytic viruses optimize immunotherapies by modulating the tumor microenvironment and affecting multiple steps in the cancer-immunity cycle, making them an attractive agent for combination strategies. We engineered an HSV-1-based oncolytic virus and investigated its antitumor effects in combination with the marketed PD-1 antibody Keytruda (pembrolizumab) in hPD-1 knock-in mice bearing non-immunogenic B16-F10 melanoma. Our results showed enhanced CD8+ and CD4+ T cell infiltration, IFN-γ secretion and PD-L1 expression in tumors, subsequently leading to the prolonged overall survival of mice. Systemic changes in lymphocyte cell proportions were also observed in the peripheral blood. In summary, these findings provide evidence that oncolytic viruses can be engineered as a potential platform for combination therapies, especially to treat tumors that are poorly responsive to immune checkpoint therapy. 1 An oncolytic virus VT09X optimizes the anti-PD-1 antibody therapy in low immunogenic melanoma. 2 Humanized PD-1 knock-in mice were used for in vivo study against melanoma. 3 Stimulation of TIL in local tumors and peripheral blood was performed. 4 Several molecule expressions relative to T cell response such as β2M and IFN-γ were evaluated. [ABSTRACT FROM AUTHOR]

Oncolytic viruses as cancer vaccines modulate the tumor microenvironment and act synergistically with immune checkpoint inhibitors to overcome resistance. Taking advantage of the loading capacity for exogenous genes, we generated a recombinant herpes simplex virus type 1 (HSV-1), HSV-aPD-1, carrying a full-length humanized anti-PD-1 monoclonal antibody (anti-PD-1 mAb) that replicates and expresses anti-PD-1 mAbs in tumor cells in vitro and in vivo. Its anti-tumor effect was assessed in human PD-1 knock-in mice by analyzing tumor inhibition, cell populations and RNA expression in tumors, and serum cytokine levels. Enhanced anti-tumor immune responses and T-cell infiltration were induced by HSV-aPD-1 compared with unloaded virus or anti-PD-1 therapy in both MC38 and B16-F10 models, resulting in improved treatment efficacy in the latter. Moreover, compared with unloaded HSV-1 or HSV-1 loaded with GM-CSF/IL-2 combined with anti-PD-1 mAbs, HSV-aPD-1 displayed similar therapeutic control of tumor growth. Finally, tumor RNAseq analysis in the B16-F10 model showed upregulated IFN pathway and antigen processing and presentation genes, and downregulated angiogenesis and cell adhesion genes, which all contribute to tumor inhibition. These findings indicate the clinical potential of HSV-aPD-1 as monotherapy or combination therapy, especially in tumors resistant to immune checkpoint inhibitors. [ABSTRACT FROM AUTHOR]

The main objectives of this study are to conduct principle analysis of mix design and evaluate the performance of the Buton rock asphalt (BRA) modified Superpave mixture through wheel tracking test, freeze–thaw indirect tensile strength ratio test, bending beam test, dynamic modulus test, and flow number (FN) test. The results prove that the voids in mineral aggregate (VMA) and the initial asphalt content calculated using the new equations proposed by this study based on theoretical analysis are more accurate than those of the traditional Superpave’s empirical equations. The high temperature performance and the moisture damage resistance of the Superpave mixture modified with BRA were improved, but the low temperature performance was slightly declined comparing with the control mixture. The values of E ∗ /sinφ from dynamic modulus test of the BRA modified Superpave mixture were larger than those of the control mixture at various test temperatures and loading frequencies. In conclusion, the Superpave mixture modified by BRA has excellent high temperature performance. [ABSTRACT FROM AUTHOR]

[Display omitted] • The nanogel DOX@Mn-Alg achieved synergistic chemo/chemodynamic therapy. • The DOX@Mn-Alg self-supplied H 2 O 2 via overexpression of NOX2 and NOX4. • The DOX@Mn-Alg can boost systemic antitumor immune response. As an interesting alternative to traditional cancer therapies, chemodynamic therapy (CDT) can kill cancer cells via the conversion of endogenous hydrogen peroxide (H 2 O 2) into highly toxic hydroxyl radicals (⋅OH). However, the slow release of catalyst ions and insufficient H 2 O 2 levels severely limit the performance of CDT. To address these issues, we explored the doxorubicin (DOX)-loaded manganese-alginate nanogel DOX@Mn-Alg with self-supplying H 2 O 2 capability by using a microfluidic chip. After internalization into tumor cells, DOX@Mn-Alg quickly releases DOX in a pH-responsive manner. The released DOX can not only kill tumor cells directly but also improve Mn2+-mediated CDT by supplying H 2 O 2 within the tumor cells. As a result, the DOX@Mn-Alg showed synergetic antitumor activity without causing distinct systemic toxicity, and also achieved T 1 -weighted magnetic resonance imaging (MRI) enhancement for cancer diagnosis. Moreover, DOX@Mn-Alg treatment can promote DC maturation and increase tumor infiltration of CD8+ T cells. It is believed that these Mn2+-chelating nanogels with the ability to self-supply H 2 O 2 can provide additional strategy for synergetic CDT therapy and also exhibit a promising potential for cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Abstract: rs151290 in KCNQ1 and rs972283 in KLF14 have been evaluated in terms of risk of type 2 diabetes mellitus (T2DM), but the results are inconsistent. We performed an meta-analysis to assess the contributions of rs151290 in KCNQ1 and rs972283 in KLF14 to risk of T2DM. We searched the worldwide literature published from 2008 to 2013 in MEDLINE via PubMed, EMBASE, Cochrane CENTRAL and Chinese databases. Two reviewers extracted data independently using a standardized protocol, and any discrepancies were resolved by a third reviewer. Fixed- and random-effects meta-analyses were performed to pool the odds ratios (ORs). Publication bias and heterogeneity were examined. A total of 11 articles were included in the meta-analysis: 6 studies with 6696 cases and 7151 controls investigated rs151290 in KCNQ1, and 5 studies with 50,552 cases and 106,535 controls investigated rs972283 in KLF14. We obtained highly significant ORs for the risk allele C for rs151290 and the risk allele G for rs972283. The population attributable risk percentage for rs151290 and rs972283 was 6.83% and 4.18%, respectively. The risk allele C of rs151290 in KCNQ1 and risk allele G of rs972283 in KLF14 were both associated with increased risk of T2DM in a global population. [Copyright &y& Elsevier]

• This was a large sample study of 538,500 individuals to investigate the prevalence of anxiety in students. • The prevalence of anxiety symptoms among chinese primary school students was higher at 13.4%. • After adjusting for potential confounders, school location, knowledge and protective practices of COVID-19 were found to be associated with anxiety symptoms. • Good knowledge of COVID-19 was associated with a lower prevalence rate, which was higher in rural areas, but there was little difference between levels of protection practice. This study was conducted on elementary school students in Henan Province, China, from February 4th to 11th, 2020, during the coronavirus disease 2019 (COVID-19) epidemic. The purpose of the study was to examine the prevalence of anxiety among students and identify the related risk factors contributing to anxiety. Demographic information and psychological status were assessed by using self-reported measures. The generalized anxiety disorder tool (GAD-7) and a multiple logistic regression model were used to assess anxiety and identify potential influencing factors. Cross-sectional data indicated that the overall anxiety prevalence was 13.4%. The prevalence of anxiety symptoms was highest among rural primary school students and lowest among city students. Three groups of students in different regions were surveyed, and the prevalence of anxiety symptoms was significantly higher among students with poor knowledge of COVID-19 than among students with good knowledge of COVID-19. After adjusting for potential confounding factors, it was found that location, knowledge, and practice were related to anxiety. This study showed that the prevalence of anxiety symptoms was higher among Chinese primary school students. The influencing factors found in this study may help relevant staff improve the mental health of children during the epidemic. [ABSTRACT FROM AUTHOR]