Universal and One-Step Modification to Render Diverse Materials Bioactivation.

Bioactive materials that can support cell adhesion and tissue regeneration are greatly in demand in clinical applications. Surface modification with bioactive molecules is an efficient strategy to convert conventional bioinert materials into bioactive materials. However, there is an urgent need to find a universal and one-step modification strategy to realize the above transformation for bioactivation. In this work, we report a universal and one-step modification strategy to easily modify and render diverse materials bioactivation by dipping materials into the solution of dibutylamine-DOPA-lysine-DOPA (DbaYKY) tripeptide-terminated cell-adhesive molecules, ß-peptide polymer, or RGD peptide for only 5 min. This strategy provides materials with a stable surface modification layer and does not cause an undesired surface color change like the widely used polydopamine coating. This one-step strategy can endow material surfaces with cell adhesion properties without concerns on nonspecific conjugation of proteins and macromolecules. This universal and one-step surface bioactivation strategy implies a wide range of applications in implantable biomaterials.

Bispecific antibody targeting both B7-H3 and PD-L1 exhibits superior antitumor activities.

Clinical application of PD-1 and PD-L1 monoclonal antibodies (mAbs) is hindered by their relatively low response rates and the occurrence of drug resistance. Co-expression of B7-H3 with PD-L1 has been found in various solid tumors, and combination therapies that target both PD-1/PD-L1 and B7-H3 pathways may provide  additional therapeutic benefits. Up to today, however, no bispecific antibodies targeting both PD-1 and B7-H3 have reached the clinical development stage. In this study, we generated a stable B7-H3×PD-L1 bispecific antibody (BsAb) in IgG1-VHH format by coupling a humanized IgG1 mAb against PD-L1 with a humanized camelus variable domain of the heavy-chain of heavy-chain antibody (VHH) against human B7-H3. The BsAb exhibited favorable thermostability, efficient T cell activation, IFN-γ production, and antibody-dependent cell-mediated cytotoxicity (ADCC). In a PBMC humanized A375 xenogeneic tumor model, treatment with BsAb (10 mg/kg, i.p., twice a week for 6 weeks) showed enhanced antitumor activities compared to monotherapies and, to some degree, combination therapies. Our results suggest that targeting both PD-1 and B7-H3 with BsAbs increases their specificities to B7-H3 and PD-L1 double-positive tumors and induces a synergetic effect. We conclude that B7-H3×PD-L1 BsAb is favored over mAbs and possibly combination therapies in treating B7-H3 and PD-L1 double-positive tumors.

Integrated analysis of transcriptomics and metabolomics of peach under cold stress.

Low temperature is one of the environmental factors that restrict the growth and geographical distribution of peach (Prunus persica L. Batsch). To explore the molecular mechanisms of peach brunches in response to cold, we analyzed the metabolomics and transcriptomics of 'Donghe No.1' (cold-tolerant, CT) and '21st Century' (cold-sensitive, CS) treated by different temperatures (-5 to -30°C) for 12 h. Some cold-responsive metabolites (e.g., saccharides, phenolic acids and flavones) were identified with upregulation only in CT. Further, we identified 1991 cold tolerance associated genes in these samples and they were significantly enriched in the pathways of 'galactose metabolism', 'phenylpropanoid biosynthesis' and 'flavonoids biosynthesis'. Weighted gene correlation network analysis showed that soluble sugar, flavone, and lignin biosynthetic associated genes might play a key role in the cold tolerance of peach. In addition, several key genes (e.g., COMT, CCR, CAD, PER and F3'H) were substantially expressed more in CT than CS under cold stress, indicating that they might be major factors during the adaptation of peach to low temperature. This study will not only improve our understanding towards the molecular mechanisms of peach trees under cold stress but also contribute to the screening and breeding program of peach in the future.

Development of a variant of dinutuximab with enhanced antitumor efficacy and reduced induction of neuropathic pain.

Dinutuximab (ch14.18) was the first approved monoclonal antibody against the tumor-associated antigen disialoganglioside GD2. Despite its success in treating neuroblastoma (NB), it triggers a significant amount of neuropathic pain in patients, possibly through complement-dependent cytotoxicity (CDC). We hypothesized that modifying ch14.18 using antibody engineering techniques, such as humanization, affinity maturation, and Fc engineering, may enable the development of next-generation GD2-specific antibodies with reduced neuropathic pain and enhanced antitumor activity. In this study we developed the H3-16 IgG1m4 antibody from ch14.18 IgG1. H3-16 IgG1m4 exhibited enhanced binding activity to GD2 molecules and GD2-positive cell lines as revealed by ELISA, and its cross-binding activity to other gangliosides was not altered. The CDC activity of H3-16 IgG1m4 was decreased, and the antibody-dependent cellular cytotoxicity (ADCC) activity was enhanced. The pain response after H3-16 IgG1m4 antibody administration was also reduced, as demonstrated using the von Frey test in Sprague-Dawley (SD) rats. In summary, H3-16 IgG1m4 may have potential as a monoclonal antibody with reduced side effects.

Performance-Based Evaluation of Healing Efficiency on Mechanical Properties of Self-Healing Cementitious Materials Incorporated with PMMA/Epoxy Microcapsule.

In this study, based upon the investigation of its effect on workability and the mechanical property of cementitious materials, the Box-Behnken design was adopted to establish models describing self-healing performance on mechanical properties of cementitious materials with polymethylmethacrylate (PMMA)/epoxy microcapsule in terms of healing rate of peak strength (Y1), the recovery rate of peak strength (Y2), the healing rate of Young's modulus (Y3), the recovery rate of Young's modulus (Y4), the healing rate of peak strain (Y5), and recovery rate of peak strain (Y6). This was performed under the influence of the four factors, including microcapsule size (X1), microcapsule content (X2), pre-loading (X3), and curing age (X4). The results showed the four factors significantly affect the healing rate and recovery rate of the peak strength, Young's modulus, and peak strain, except the healing rate on peak strain. Moreover, the interaction between the factors showed some influence as well. The numerically optimised values of X1, X2, X3, and X4 are 203 nm, 5.59%, 43.56%, and 21 days, respectively, and the self-healing cementitious materials with desirable mechanical characteristics (Y1 63.67%, Y2 145.22%, Y3 40.34%, Y4 132.22%, Y5 27.66%, and Y6 133.84%) with the highest desirability of 0.9050 were obtained. Moreover, the porosity of the specimen confirmed the healing performance of PMMA/epoxy microcapsules in cementitious materials.

NGF monoclonal antibody DS002 alleviates chemotherapy-induced peripheral neuropathy in rats.

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the pervasive side effects of chemotherapy, leading to poor quality of life in cancer patients. Discovery of powerful analgesics for CIPN is an urgent and substantial clinical need. Nerve growth factor (NGF), a classic neurotrophic factor, has been identified as a potential therapeutic target for pain. In this study, we generated a humanized NGF monoclonal antibody (DS002) that most effectively blocked the interaction between NGF and tropomyosin receptor kinase A (TrkA). We showed that DS002 blocked NGF binding to TrkA in a dose-dependent manner with an IC50 value of 6.6 nM; DS002 dose-dependently inhibited the proliferation of TF-1 cells by blocking the TrkA-mediated downstream signaling pathway. Furthermore, DS002 did not display noticeable species differences in its binding and blocking abilities. In three chemotherapy-induced rat models of CIPN, subcutaneous injection of DS002 produced a significant prophylactic effect against paclitaxel-, cisplatin- and vincristine-induced peripheral neuropathy. In conclusion, we demonstrate for the first time that an NGF inhibitor effectively alleviates pain in animal models of CIPN. DS002 has the potential to treat CIPN pain in the clinic.

A bispecific antibody targeting HER2 and PD-L1 inhibits tumor growth with superior efficacy.

Activation of the programmed cell death protein 1 and programmed cell death ligand 1 (PD-1/PD-L1) signaling axis plays important roles in intrinsic or acquired resistance to human epidermal growth factor receptor 2 (HER2)-directed therapies in the clinic. Therefore, therapies simultaneously targeting both HER2 and PD-1/PD-L1 signaling pathways are of great significance. Here, aiming to direct the anti-PD-L1 responses toward HER2-expressing tumor cells, we constructed a humanized bispecific IgG1 subclass antibody targeting both HER2 and PD-L1 (HER2/PD-L1; BsAb), which displayed satisfactory purity, thermostability, and serum stability. We found that BsAb showed enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) activity in vitro. In the late phase of peripheral blood mononuclear cell (PBMC)-humanized HER2+ tumor xenograft models, BsAb showed superior therapeutic efficacies as compared with monoclonal antibodies (mAbs) or combination treatment strategies. In cynomolgus monkeys, BsAb showed favorable pharmacokinetics and toxicity profiles when administered at a 10 mg/kg dosage. Thus, HER2/PD-L1 BsAb was demonstrated as a potentially effective option for managing HER2+ and trastuzumab-resistant tumors in the clinic. We propose that the enhanced antitumor activities of BsAb in vivo may be due to direct inhibition of HER2 signaling or activation of T cells.

Ellagic acid inhibits high glucose-induced injury in rat mesangial cells via the PI3K/Akt/FOXO3a signaling pathway.

The pathological damage of mesangial cells serves an important role in the occurrence and development of diabetic nephropathy. Ellagic acid has been reported to possess antioxidant, antitumor, antiviral and anti-inflammatory properties in several diseases, but the roles of ellagic acid in diabetic nephropathy are unclear. The main aim of the present study was to investigate the effect of ellagic acid on high glucose-induced mesangial cell damage. The results revealed that high glucose could induce the hyperproliferation of mesangial cells, decrease the activity of superoxide dismutase, increase the malondialdehyde content, the level of reactive oxygen species, the secretion of inflammatory factors (TNF-α, IL-1ß and IL-6) and the synthesis of extracellular matrix (Fibronectin, MMP-9 and TIMP-1) and activate the PI3K/Akt/FOXO3a signaling pathway. Ellagic acid could attenuate the injury of mesangial cells induced by high glucose in a concentration-dependent manner and its effect was consistent with that of a PI3K inhibitor (LY294002). Moreover, a PI3K agonist (740Y-P) reversed the protective effect of ellagic acid on mesangial cells induced by high glucose. In conclusion, ellagic acid protected mesangial cells from high glucose-induced injury in a concentration-dependent manner. The mechanism may be associated with ellagic acid inhibiting the activation of the PI3K/Akt signaling pathway and reducing the expression levels of downstream transcription factor FOXO3a.

Alginate mediated functional aggregation of gold nanoclusters for systemic photothermal therapy and efficient renal clearance.

For renal clearable nanoagents, it is challenging to delay the renal clearance to acquire efficient tumor accumulation. Herein, we report sodium alginate (SA) stabilized gold (Au) NCs. The Au NCs are of high biocompatibility and renal clearable. Contributed from the ligands of SA, the half-life (t1/2) of Au NCs is prolonged to ∼9.3 h, enhancing the tumor accumulation rate to 10.4 %ID/g. In tumor microenvironment (TME), the Au NCs are stimulated to functionally aggregate, which switches on the photothermal effect. Animal experiments prove that Au NCs aggregates are efficient photothermal therapy (PTT) agents for both local treatment of single tumors and systemic treatment of double-tumor models without causing noticeable side effects, confirming the biosecurity of Au NCs and systemic PTT. The switchable strategy of PTT may signify the establishment of a new systemic therapeutic methodology.

miR-25-3p promotes proliferation and inhibits autophagy of renal cells in polycystic kidney mice by regulating ATG14-Beclin 1.

MicroRNAs are involved in the regulation of the autophagy and proliferation in several diseases. This study aims to verify the role of miR-25-3p in the proliferation and autophagy of renal cells in polycystic kidney disease (PKD). We found that kidney to body weight and blood urea content were increased in PKD mice. Cystic dilations were increased in kidney tissue from PKD mice, and autophagy-related protein ULK1 and the ratio of LC3-II/LC3-I were decreased, indicating autophagy was inhibited in PKD mice. In addition, miR-25-3p was upregulated in PKD mice, and inhibition of miR-25-3p decreased cystic dilations in kidney tissues, increased ULK1 expression and the ratio of LC3-II/LC3-I, indicating inhibition of miR-25-3p enhanced the autophagy in PKD. Besides, inhibition of miR-25-3p suppressed the proliferation of renal cells and downregulated E2F-1 and PCNA expressions. Importantly, miR-25-3p targetedly suppressed ATG14 expression in PKD cells. Finally, silencing ATG14 abolished the inhibition effect of miR-25-3p inhibitor on renal cell proliferation, and reversed the inhibition effect of miR-25-3p inhibitor on E2F-1 and PCNA expressions in in vitro and in vivo experiments, which suggested that ATG14 was involved in the regulation of miR-25-3p-mediated kidney cell proliferation. Therefore, inhibition of miR-25-3p promoted cell autophagy and suppressed cell proliferation in PKD mice through regulating ATG14.

Research on the Design and Automatic Recognition Algorithm of Subsidence Marks for Close-Range Photogrammetry.

In China, traditional techniques for measuring structural subsidence cannot keep pace with the rapid development of critical national infrastructure such as the growing network of high-speed railways. Traditional monitoring methods using leveling instruments are inefficient and time consuming when monitoring structures like bridges and tunnels. Thus, a fast, economical, and more accurate and precise way to survey building subsidence is urgently needed to address this problem. This paper introduces a new close-range photogrammetry technique that deploys a fixed camera with tilt compensator to measure changes in height over small areas. A barcode subsidence mark that can be identified automatically during digital image processing replaces the leveling points used in traditional methods. Four experiments at different locations verified that results from the new method were stable and consistent with total station measurements. This approach is simple, inexpensive, and produces accurate and precise results as our evaluation results show.

5S Multifunctional Intelligent Coating with Superdurable, Superhydrophobic, Self-Monitoring, Self-Heating, and Self-Healing Properties for Existing Construction Application.

There is a constant drive to develop ultra-high-performance multifunctional coatings for existing construction used in modern engineering technologies. For these materials to be used in unsound infrastructure protections, they are required to present enhanced robustness while bearing functionalities to meet multiple uses. Single-function coating is not smart enough to provide satisfactory protection, and the preparation process of multifunctional materials is complex, costly, and provides poor durability. Thus, existing coatings are not suitable to generate an intelligent closed-loop protection system. Herein, we report an innovative 5S multifunctional intelligent coating (5SC) for existing construction materials with superdurable, superhydrophobic, self-monitoring, self-heating, and self-healing properties. The 5SC material showed highly durable superhydrophobic properties as revealed by the main failure tests of building materials including physical friction (abrasion, scratching), 100% tensile strain, photoaging (3000 h of ultraviolet (UV) aging), acid corrosion (concentrated hydrochloric acid and sulfuric acid), and freeze-thaw aging (salty solution). The coated surface was highly sensitive to pressure, with monitoring thresholds from 1 to 30 000 N per 0.01 m2. It showed an early heating rate as high as 6 °C/min while maintaining very good self-monitoring and ice-melting drainage performance to protect the existing structures. This novel composite material is suitable for constructions in extreme areas where corrosion and freeze-thaw damage can occur. This multifunctional material presents a very broad range of applications and development potential in the construction field.

Interface Properties of Nanosilica-Modified Waterborne Epoxy Cement Repairing System.

Nowadays, numerous concrete structures are urgently needed to be repaired and strengthened for the severe safety and durability of constructions. In this study, a novel type of silane-based interfacial coupling agent (ICA) is prepared by modifying the silane coupling agent (SCA) with a hydrothermally treated nanosilica (HTNS). The effect of ICA on the cement hydration and crystalline form as well as the hydrolysis/condensation extent of siloxanes is illustrated. The bonding strength, morphology and propagation of the interface cracks, and the interfacial ductile fracture characterization are investigated. Besides, the coupling mechanism of ICA in the repaired interface is explored. The results show that HTNS effectively catalyzes SCA hydrolysis and condensation to form Si-O-Si bonding in a neutral environment. The application of ICA on an old cementitious matrix not only significantly improves the bonding strength and toughness of the repair interface, but also mitigates the negative effect of dealcoholization of siloxanes on the hydration of the cement. The repaired interface simultaneously exhibits stiffness, toughness, and multicracking features in the process of straining. On a microlevel, ICA consumes portlandite during cement hydration and finely crystallizes to form a layered plug structure at the repaired interface . With the continuous dissolution of portlandite, the nanosilica in ICA forms a fibrous, stable product with ions and enhances the interfacial pore plug effect.

Long Noncoding RNA PVT1 Promotes Non-Small Cell Lung Cancer Cell Proliferation through Epigenetically Regulating LATS2 Expression.

Long noncoding RNAs (lncRNA) are a novel class of transcripts with no protein coding capacity, but with diverse functions in cancer cell proliferation, apoptosis, and metastasis. The lncRNA PVT1 is 1,716 nt in length and located in the chr8q24.21 region, which also contains the myelocytomatosis (MYC) oncogene. Previous studies demonstrated that MYC promotes PVT1 expression in primary human cancers. However, the expression pattern and potential biologic function of PVT1 in non-small cell lung cancer (NSCLC) is still unclear. Here, we found that PVT1 was upregulated in 105 human NSCLC tissues compared with normal samples. High expression of PVT1 was associated with a higher tumor-node-metastasis stage and tumor size, as well as poorer overall survival. Functional analysis revealed that knockdown of PVT1 inhibited NSCLC cell proliferation and induced apoptosis both in vitro and in vivo RNA immunoprecipitation and chromatin immunoprecipitation assays demonstrated that PVT1 recruits EZH2 to the large tumor suppressor kinase 2 (LATS2) promoter and represses LATS2 transcription. Furthermore, ectopic expression of LATS2 increased apoptosis and repressed lung adenocarcinoma cell proliferation by regulating the Mdm2-p53 pathway. Taken together, our findings indicated that PVT1/EZH2/LATS2 interactions might serve as new target for lung adenocarcinoma diagnosis and therapy. Mol Cancer Ther; 15(5); 1082-94. ©2016 AACR.

The Long Noncoding RNA MEG3 Contributes to Cisplatin Resistance of Human Lung Adenocarcinoma.

Long noncoding RNAs (lncRNAs) have been identified as oncogenes or tumor suppressors that are involved in tumorigenesis and chemotherapy drug resistance. Maternally expressed gene 3 (MEG3) is an imprinted gene located at 14q32 that encodes an lncRNA, and decreased MEG3 expression plays an important role in multiple cancers. However, its biological role in the development of the chemoresistance phenotype of human lung adenocarcinoma (LAD) is unknown. This study aimed to observe the expression of MEG3 in LAD and to evaluate its biological role and clinical significance in the resistance of LAD cells to cisplatin. MEG3 expression was markedly decreased in cisplatin-resistant A549/DDP cells compared with parental A549 cells as shown by an lncRNA microarray. MEG3 overexpression in A549/DDP cells increased their chemosensitivity to cisplatin both in vitro and in vivo by inhibiting cell proliferation and inducing apoptosis. By contrast, MEG3 knockdown in A549 cells decreased the chemosensitivity. Moreover, MEG3 was decreased in cisplatin-insensitive LAD tissues while p53 protein levels were decreased and Bcl-xl protein levels increased. Furthermore, patients with lower levels of MEG3 expression showed worse responses to cisplatin-based chemotherapy. These findings demonstrate that MEG3 is significantly downregulated in LAD and partially regulates the cisplatin resistance of LAD cells through the control of p53 and Bcl-xl expression. Thus, MEG3 may represent a new marker of poor response to cisplatin and could be a potential therapeutic target for LAD chemotherapy.