NUMERICAL INVESTIGATION OF GLASS-FIBER REINFORCED PLASTIC MORTAR PIPES CULVERT RESPONSE TO HEAVY TRUCK LOADS

The main objective of this paper is to investigate the dynamic performance and behaviour of glass-fiber reinforced plastic (GRP) mortar pipes under heavy truck loads. According to the field conditions, a finite element dynamic analysis (FEDA) model of GRP pipe culverts was established. Modal analysis of the vibration system was carried out, and the main natural frequencies with 26.6Hz,32Hz,35.7Hz and corresponding mode shapes were obtained. On the basis of modal analysis, dynamic response of GRP pipe culverts under vehicle loads was simulated through random vibration. Based on the measured vibration velocity time histories, the modal and random vibration responses of the vibration system were analyzed. The results show that the spectral response value of pipeline to vehicle load decreases with the increase of buried depth. When the depth of GRP pipe culverts buried is greater than 0.8m, the influence of ground vehicle dynamic loads on the vibration of GRP pipe culverts cannot be taken into consideration. It can provide the basis for the design of GRP pipe culverts, especially under heavy loads

Tumor-targeted upconverting nanoplatform constructed by host-guest interaction for near-infrared-light-actuated synergistic photodynamic-/chemotherapy

The strategic combination of photodynamic therapy and chemotherapy has emerged as a promising treatment option for various tumor indications, which not only expands our understanding of each individual modality but also reveals new opportunities to achieve superadditive benefit via exploring their internal synergy rather than simple mixing. In this study, dual-emissive upconverting nanoparticle (UCNP) was employed to bridge the two treatment regimens to synergistically reinforce the therapeutic efficacy. The UCNP-based drug delivery nanoplatform was first co-loaded with 1,8-dihydroxy-3-methylanthraquinone (DHMA) photosensitizers and UV-activatable camptothecin prodrug (NBCCPT) and then complexed with biofunctional β-cyclodextrin species (β-CD-PEG-LA) via highly specific host-guest interactions to cap the camptothecin prodrug conjugated on the nanoparticle surface. The supramolecularly attached β-CD-PEG-LA could not only enhance the aqueous dispersity of the nanocarriers and prevent DHMA leakage, but also imbues targeting effect against asialoglycoprotein receptor-overexpressing tumor cells. The UCNP core would convert the NIR excitation (980 nm) into localized UV (360 nm) and visible (480 nm) emissions, of which the former would cleave the nitrobenzene linker to restore the cytotoxicity of CPT while the latter could excite the photosensitizer to generate reactive oxygen species (ROS). In addition to the photodynamic damage, the light-generated ROS could also facilitate the endo/lysosomal escape of the endocytosed nanoparticles and improve the overall antitumor potency in a synergistic manner.Agency for Science, Technology and Research (A*STAR)National Research Foundation (NRF)This research is supported by the National Natural Science Foundation of China (11832008, 51773023, 51602034, 51603024, 51825302, 21734002), National Key R&D Program of China (2016YFC1100300, 2017YFB0702603), Innovation Project on Industrial Generic Key Technologies of Chongqing (cstc2015zdcy-ztzx120003), Natural Science Foundation of Chongqing Municipal Government (cstc2018jcyjAX0368), People's Livelihood Special Innovation Projects of Chongqing CSTC (cstc2017shmsA130071), Fundamental Research Funds for the Central Universities (2018CDQYSM0036), Innovation Team in University of Chongqing Municipal Government (CXTDX201601002), Singapore Agency for Science, Technology and Research (A*STAR) AME IRG grant (A1883c0005) and the Singapore National Research Foundation Investigatorship (NRF-NRFI2018-03)

Comparison of minimally invasive transforaminal lumbar interbody fusion (Mis-TLIF) with bilateral decompression via unilateral approach and open-TLIF with bilateral decompression for degenerative lumbar diseases: a retrospective cohort study

Abstract Objective Presently, no study has compared the clinical outcomes of minimally invasive transforaminal lumbar interbody fusion (Mis-TLIF) with bilateral decompression via the unilateral approach (BDUA) and Open-TLIF with bilateral decompression for degenerative lumbar diseases (DLD). We aimed to compare the clinical outcomes of through Mis-TLIF combined with BDUA and Open-TLIF with bilateral decompression for the treatment of DLD, and reported the learning curve of the procedure of MIS-TLIF with BDUA. Methods We retrospectively analyzed the prospectively collected data of consecutive DLD patients in the two groups from January 2016 to January 2020. Results The operative time (OT) was significantly longer in the Mis-TLIF group (n = 113) than in the Open-TLIF group (n = 135). The postoperative drainage volume (PDV) and length of stay (LOS) were significantly higher in the Open-TLIF group than in the Mis-TLIF group. Additionally, the complication rate was significantly higher in the Open-TLIF group than in the Mis-TLIF group (14.8% vs. 6.2%, P = 0.030), while there was no significant difference in the reoperation and adjacent segment disease rates between the two groups. There were no significant differences in back pain and leg pain Numerical Rating Scale (NRS) scores and Oswestry Disability Index (ODI) between the two groups preoperatively, at discharge, and 2 years postoperatively. Patients in both groups showed significant improvements in NRS scores and ODI scores after surgery. OT was negatively correlated with the number of surgeries performed (P < 0.001, r =  −0.43). The learning curve of Mis-TLIF with BDUA was steep, with OT tapered to steady state in 43 cases. Conclusion Compared with Open-TLIF with bilateral decompression, Mis-TLIF with BDUA can achieve equivalent clinical outcomes, lower PDV and LOS, and lower complication rates. Although this procedure took longer, it could be a viable alternative for the treatment of DLD after a steep learning curve

Cell-specific metabolic reprogramming of tumors for bioactivatable ferroptosis therapy

Ferroptosis is a nonapoptotic iron-dependent cell death pathway with a significant clinical potential, but its translation is impeded by lack of tumor-specific ferroptosis regulators and aberrant tumor iron metabolism. Herein, we report a combinational strategy based on clinically tested constituents to selectively induce ferroptosis in metabolically reprogrammed tumor cells through cooperative GPX4-inhibition and ferritinophagy-enabled Fe2+ reinforcement. Azido groups were first introduced on tumor cells using biocompatible long-circulating self-assemblies based on polyethylene glycol-disulfide-N-azidoacetyl-d-mannosamine via metabolic glycoengineering. The azido-expressing tumor cells could specifically react with dibenzocyclooctyne-modified disulfide-bridged nanoassemblies via bioorthogonal click reactions, where the nanoassemblies were loaded with ferroptosis inducer RSL3 and ferritinophagy initiator dihydroartemisinin (DHA) and could release them in a bioresponsive manner. DHA-initiated ferritinophagy could degrade intracellular ferritin to liberate stored iron species and cooperate with the RSL3-mediated GPX4-inhibition for enhanced ferroptosis therapy. This tumor-specific ferroptosis induction strategy provides a generally applicable therapy with enhanced translatability, especially for tumors lacking targetable endogenous receptors.National Research Foundation (NRF)This study is financially supported by the National Natural Science Foundation of China (32122048, 11832008, 92059107, and 51825302), the Chongqing Graduate Scientific Research and Innovation Program (cYB20047 and cYS20043), the Fundamental Research Funds for the Central Universities (2021CDJLXB001, 2021CDJZYJH-002, and 2020CDJYGZL009), the Chongqing Outstanding Young Talent Supporting Program (cstc2021ycjh-bgzxm0124), the Returning Overseas Scholar Innovation Program (CX2018062, CX2021098, and CX2020045), the Natural Science Foundation of Chongqing Municipal Government (cstc2020jcyj-msxmX0834 and cstc2021jcyj-jqX0022), and the Singapore National Research Foundation Investigatorship (NRF-NRFI2018-03) and Competitive Research Programme (CRP26-2021-0058)

Light-responsive prodrug-based supramolecular nanosystems for site-specific combination therapy of cancer

On-demand release of chemotherapeutic drugs from their prodrugs triggered by light irradiation has been attracting great attention for effective cancer treatment. Herein, we prepared prodrug based supramolecular nanoparticles (HA−aPS−aCPT) composed of (1) β-cyclodextrin conjugated hyaluronic acid polymer (HA−CD), (2) adamantane-modified camptothecin prodrug (aCPT) caged via reactive oxygen species (ROS) responsive thioketal linker, and (3) adamantane modified photosensitizer (aPS), for combination photodynamic therapy and light-controlled chemotherapy. aCPT could release free camptothecin by the cleavage of ROS-sensitive thioketal linker. aPS is employed to produce ROS under light irradiation. HA−aPS−aCPT nanoparticles are formed by supramolecular means with excellent colloidal stability and monodispersity in aqueous solution. Confocal imaging and flow cytometric analysis confirm the selective uptake of HA−aPS−aCPT nanoparticles via CD44 receptor-mediated endocytosis by MDA-MB-231 cells, on account of the targeting capability of hyaluronic acid. Cell viability assays show that HA−aPS−aCPT nanoparticles possess minimal cytotoxicity in the dark, while presenting high cellular toxicity under light irradiation. In vivo experiments exhibit selective accumulation of HA−aPS−aCPT nanoparticles in MDA-MB-231 tumor of nude mice. Significant tumor regression is observed when light irradiation is applied after intravenous injection of HA−aPS−aCPT nanoparticles. Thus, HA−aPS−aCPT nanoparticles demonstrate a great potential for on-demand combination photodynamic therapy and chemotherapy of tumor.NRF (Natl Research Foundation, S’pore)ASTAR (Agency for Sci., Tech. and Research, S’pore)MOE (Min. of Education, S’pore)Accepted versio

Tumor‐Microenvironment‐Activated In Situ Self‐Assembly of Sequentially Responsive Biopolymer for Targeted Photodynamic Therapy

A sequentially responsive photosensitizer-integrated biopolymer is developed for tumor-specific photodynamic therapy, which is capable of forming long-retained aggregates in situ inside tumor tissues. Specifically, the photosensitizer zinc phthalocyanine (ZnPc) is conjugated with polyethylene glycol (PEG) via pH-labile maleic acid amide linker and then immobilized onto the hyaluronic acid (HA) chain using a redox-cleavable disulfide linker. The PEG segment can enhance blood circulation of the molecular carrier after intravenous administration and be shed after reaching the acidic tumor microenvironment, allowing the remaining fragment to self-assemble into large clusters in situ to avoid backward diffusion and improve tumor retention. This process is driven by hydrophobic interactions and does not require additional external actuation. The aggregates are then internalized by the tumor cells via HA-facilitated endocytosis, and the high glutathione level in tumor cells eventually leads to the intracellular release of ZnPc to facilitate its interaction with the subcellular lipid structures. This tumor-triggered morphology-based delivery platform is constructed with clinically tested components and could potentially be applied to other hydrophobic therapeutics.National Research Foundation (NRF)Accepted versionX. Wang and M.H. Li contributed equally to this work. This work was financially supported by Natural Science Foundation of China (11832008, 51773023 and 21734002), National Key Technology R&D Program of China (2017YFB0702603 and 2016YFC1100300), Fundamental Research Funds for the Central Universities (2019CDQYSW005), Chongqing Outstanding Young Talent Supporting Program (CQYC201905072), Returning Overseas Scholar Innovation Program (CX2018062), Central University's Basic Scientific Research Business Fee Medical Integration Project (2019CDYGYB004). The work was also supported by the Singapore National Research Foundation Investigatorship (NRF-NRFI2018-03)

miR-202-3p Regulates Sertoli Cell Proliferation, Synthesis Function, and Apoptosis by Targeting LRP6 and Cyclin D1 of Wnt/β-Catenin Signaling

MicroRNAs (miRNAs) play important roles in mammalian spermatogenesis, which is highly dependent on Sertoli cells. However, the functions and mechanisms of miRNAs in regulating human Sertoli cells remain largely unknown. Here, we report that hsa-miR-202-3p mediates the proliferation, apoptosis, and synthesis function of human Sertoli cells. miR-202-3p was upregulated in Sertoli cells of Sertoli cell-only syndrome (SCOS) patients compared with obstructive azoospermia (OA) patients with normal spermatogenesis. Overexpression of miR-202-3p induced Sertoli cell apoptosis and inhibited cell proliferation and synthesis, and the effects were opposite when miR-202-3p was knocked down. Lipoprotein receptor-related protein 6 (LRP6) and Cyclin D1 of the Wnt/β-catenin signaling pathway were identified as direct targets of miR-202-3p in Sertoli cells, which were validated by bioinformatics tools and dual-luciferase reporter assay. Differentially expressed LRP6 and Cyclin D1 between OA and SCOS Sertoli cells were also verified. LRP6 small interfering RNA (siRNA) interference not only mimicked the effects of miR-202-3p overexpression, but also antagonized the effects of miR-202-3p inhibition on Sertoli cells. Collectively, miR-202-3p controls the proliferation, apoptosis, and synthesis function of human Sertoli cells via targeting LRP6 and Cyclin D1 of the Wnt/β-catenin signaling pathway. This study thus provides a novel insight into fate determinations of human Sertoli cells and niche of human testis. Keywords: human Sertoli cells, miR-202-3p, proliferation and apoptosis, synthesis, LRP6, Cyclin D1, Wnt/β-cateni