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To improve the intrinsic electronic conductivity of Na3V2(PO4)2F3 (NVPF), zirconium (Zr) was introduced into the NVPF/C compound through a carbothermal reduction reaction with citric acid as the carbon source. The effects of Zr4+ doping on the crystal structure and morphology of the as-prepared materials were analyzed. Electrochemical and kinetic properties of the samples were investigated by galvanostatic charge-discharge, CV and EIS test. It is confirmed that moderate Zr4+ doping can improve the electrochemical performance of NVPF. Among all Na3V2-xZrx(PO4)2F3/C (x = 0, 0.01, 0.05, 0.1) samples, Na3V1·95Zr0·05(PO4)2F3/C shows the best rate and cycle performance. It exhibits the highest specific capacity of 121.8 and 110.3 mAh/g at 0.2 and 10 C, respectively, and maintains a capacity retention of approximately 83.6% after 1000 cycles at 5 C. The kinetic properties results show that the excellent electrochemical performance of Na3V1·95Zr0·05(PO4)2F3/C can be attributed to the increase in electronic conductivity and ion diffusion coefficient.

Na3V2(PO4)2F3 (NVPF) with NASCION (Na superionic conductor) is recognized as a potential cathode material owing to its high theoretical capacity. However, the electronic conductivity of NVPF is much lower than its ionic conductivity, which seriously affects the properties of this material. The carbon layer can be used as the conductive medium to enhance the conductivity of NVPF. In this study, we propose a single-step solid-state reaction method based on mechanical activation with pitch as the carbon source to synthesize NVPF/C composites. The crystallographic structure and morphology of all as-prepared samples were investigated by XRD, Raman spectroscopy, BET measurement, thermal analysis, SEM and TEM. Furthermore, the electrochemical performance and kinetic properties were analyzed by CV, galvanostatic charge–discharge and EIS tests. These tests outcomes demonstrated that the NVPF/C-2 composite with a carbon content of 12.14 wt% showed an excellent rate performance and cycle stability. It presented reversible capacities of 103 and 95 mA h g−1 at 0.2 and 10C, respectively, and an outstanding retention of 91.9% after 500 cycles at 5C. These excellent properties of the NVPF/C-2 composite are attributed to its high ion diffusion coefficient and small charge transfer impedance.

In biological imaging, the use of long-wavelength-emitting (>650 nm) fluorescent probes can significantly reduce the interference from cell auto-fluorescence and thus greatly improve the imaging resolution because intrinsic biomolecules rarely absorb light and emit fluorescence in the long-wavelength region. In this work, a long-wavelength-emitting two-photon fluorescent probe (TTNO) for nitric oxide (NO) detection in living cells is designed and synthesized. TTNO shows ∼28-fold enhanced fluorescence intensity (at 658 nm) with a low detection limit of 9 nM, a fast response to NO within ∼40 seconds and a high selectivity for NO. In addition, it is worth mentioning that TTNO can also be excited with near-infrared light via two-photon absorption. Its biological application for real-time imaging of exogenous and endogenous NO in living cells is successfully demonstrated by using one-photon and two-photon microscopy, respectively.

Small interfering RNA (siRNA) that mediates target gene silencing through RNA interference (RNAi) has attracted increasing interest in exploring gene functions as well as treating a variety of diseases. However, the inefficient delivery of the unstable and negatively charged siRNA into cells restricts the progress of the RNAi-based therapeutics. In this work, we describe the development of a nanoplatform based on conjugated polymer dots (Pdots) for efficient siRNA delivery. The cationic lipid G0C14 was introduced in the Pdots for siRNA complexing. The G0C14-containing polymer dots (G-Pdots) not only retained the outstanding fluorescence properties but also enhanced cellular uptake of siRNA. The positively charged G0C14 was able to interact with the negatively charged siRNA via electrostatic interactions, while the G-Pdot/siRNA complexes still remained negatively charged. A prominent property of this nanoplatform was the low cytotoxicity as compared to the commercial agent Lipofectamine, while the gene silencing efficiency was comparable. Our results indicate that biocompatible G-Pdots represent a promising platform for imaging-guided siRNA delivery.

Hypoxia is closely related to multiple diseases, especially in tumors, which increases the aggressiveness and drug resistance of cancer cells. Precise hypoxia imaging is of great significance for cancer diagnosis and the evaluation of therapeutic effects. A kind of hydrophobic polymer (i.e., PFPtTFPP) as an imaging probe for hypoxia with fluorene as an energy donor and an oxygen-sensitive PtII porphyrin as an energy acceptor was developed. Compact polymer dots (Pdots) with a small size were prepared by nanoprecipitation. The PFPtTFPP Pdots showed excellent hypoxia sensing in solution with high sensitivity and full reversibility. The emission intensity, quantum yields, lifetime, and single-particle brightness significantly increased under hypoxia conditions. Remarkably, hypoxia imaging in vitro and in vivo was realized, and a clear increase in brightness was observed under hypoxia conditions and in the tumor area. Excellent hypoxia imaging ability is beneficial to potential applications in cancer diagnosis.

We synthesized a series of acridone derivatives for specific binding ligands of i-motifs. Subsequent evaluations showed that B19 could selectively bind to and stabilize the c-myc promoter i-motif without significant binding to the G-quadruplex and duplex DNA. This caused down-regulation of c-myc transcription and expression, resulting in tumor cell apoptosis.

Context Urinary iodine (UI) is commonly used for evaluating iodine status, whereas serum iodine (SI) is more closely correlated with bioavailable iodine. However, no reliable reference intervals (RIs) for clinical use are available. We aimed to establish RIs for SI, UI, and a ratio of UI to urinary creatinine (U-Cre) applicable to the Chinese population. Methods This multicenter cross-sectional study enrolled 930 apparently healthy adults from six representative cities in China (Beijing, Dongying, Guiyang, Urumqi, Shenzhen, and Qiqihar) in 2017. Thyroid ultrasonography and thyroid function tests, including antithyroid antibody tests, were performed to exclude individuals with latent thyroid diseases. An iodine intake-related questionnaire survey was performed. SI and UI were measured using inductively coupled plasma-mass spectrometry. Possible influencing factors of iodine levels were evaluated using multiple regression analysis. Results Post-exclusion, the final analysis included 894 individuals. Seafood intake frequency was positively correlated with SI (standardized partial regression coefficient = 0.23) but not with UI and UI/U-Cre. SI was positively correlated with serum TT4 (Spearman correlation coefficient: 0.40), TT3 (0.23), and FT4 (0.18). SI and UI showed no age- or sex-specific variations. Significantly higher UI/U-Cre values were observed in Qiqihar than in Beijing, Guizhou, and Shenzhen. Shenzhen showed the lowest UI levels among all evaluated cities. With application of latent abnormal values exclusion procedurere, the RIs for SI, UI, and UI/U-Cre in the population were 36.0–79.3 μg/L, 19–385 μg/L, 22–450 μg/g, respectively. Conclusions We established RIs for UI and SI among healthy Chinese individuals with no thyroid nodule or dysfunction.

Overexpression of epidermal growth factor receptor (EGFR) is common in pancreatic cancer and associated with the poor prognosis of this malignancy. To develop anti-EGFR antibody–drug conjugates (ADCs) for use in a novel EGFR-targeting approach to treat pancreatic cancer. A humanized anti-EGFR monoclonal antibody (RC68) was generated by mouse immunization and complementary-determining region grafting technology. Two RC68-based ADCs, RC68-MC-VC-PAB-MMAE and RC68-PY-VC-PAB-MMAE, were synthesized by conjugating monomethyl auristatin E (MMAE), a small-molecule cytotoxin, to RC68 through two distinct linkers (MC and PY). Internalization of the RC68-based ADCs was examined by flow cytometry. The in vitro and in vivo antitumor activities of RC68-based ADCs were evaluated in human pancreatic cancer cells and in a BXPC-3 xenograft nude mouse model, respectively. The RC68-based ADCs bound to EGFR on the surface of tumor cells and were effectively internalized, resulting in the death of EGFR-positive cancer cell lines. The RC68-based ADCs (at 5 or 10 mg/kg) were more potent than gemcitabine hydrochloride (60 mg/kg) at inhibiting the growth of BXPC-3 xenografts. Moreover, RC68-PY-VC-PAB-MMAE was found to have superior stability in human plasma compared with RC68-MC-VC-PAB-MMAE. A novel EGFR-targeting ADC, RC68-PY-VC-PAB-MMAE, shows promise as an effective, selective, and safe therapeutic agent for EGFR-positive pancreatic cancer.

Epidermal growth factor receptor (EGFR) is highly expressed on non-small cell lung cancers (NSCLC) and a valuable therapeutic target. This study aimed at producing and characterizing monomethyl auristatin E (MMAE)-conjugated anti-EGFR antibody as a novel EGFR-targeting therapy for NSCLC. A humanized anti-EGFR monoclonal antibody (named RC68) was purified and conjugated with MMAE using a MC-VC-PAB or PY-VC-PAB linker. The in vitro and in vivo antitumor activity of RC68-MC-VC-PAB-MMAE and RC68-PY-VC-PAB-MMAE were characterized. The RC68 was generated from RC68-expressing cells and had a purity of > 99.0%. The RC68 recognized EGFR on tumor cells, particularly for higher EGFR expressing H125, A431, HCC827 and H1975 cells. The RC68 was conjugated with an average of 4 MMAE molecules to generate RC68-MC-VC-PAB-MMAE and RC68-PY-VC-PAB-MMAE, respectively. The RC68-MC-VC-PAB-MMAE, RC68-PY-VC-PAB-MMAE and RC68 displayed similar binding affinity to EGFR on tumor cells, and RC68-MC-VC-PAB-MMAE and RC68-PY-VC-PAB-MMAE were effectively internalized by H125 cells. The RC68-MC-VC-PAB-MMAE and RC68-PY-VC-PAB-MMAE inhibited the growth of H125 cells in vitro with an IC50 7.37–8.04 ng/mL and implanted H125 tumors in vivo, but did not affect body weights of mice. The antitumor effect of RC68-MC-VC-PAB-MMAE was stronger than RC68-PY-VC-PAB-MMAE, which was also stronger than docetaxel in vivo. These novel antibody–drug conjugates, particularly for RC68-MC-VC-PAB-MMAE, may be a potential candidate for treatment of EGFR + NSCLC.

B-cell lymphoma remains one of the most refractory tumors, and as such the development of novel treatment approaches, such as antibody-drug conjugates (ADCs), is required. To improve the stability and homogeneity of the ADCs, a humanized anti-CD19 monoclonal antibody (RC58) was developed in the present study. RC58 was based on the CD19 antigen as a potential molecular target of human B-cell lymphomas. RC58 has high CD19-binding affinity and can be internalized in CD19-positive cells through endocytosis. Furthermore, three types of RC58-based ADCs (ADC-1, ADC-2, and ADC-3) were generated using three kinds of Maleimide-PEG-based linkers with two different cytotoxins. The anti-tumor activities of the ADCs were confirmed by in vitro and in vivo experiments. The stability of the ADCs was also evaluated by incubation in human plasma for 10 days. In vitro experiments showed that the three ADCs had distinct inhibitory effects on several B-lymphoma cell lines. Meanwhile, a close correlation between efficacy and drug concentration was found in a nude mouse xenograft model of human B-cell lymphoma, after treatment with RC58-based ADCs. Our results suggest that ADC-1, with high efficiency, could be used as a potential therapeutic agent for human B-cell malignancies.

G-quadruplexes are four-stranded DNA structures formed from G-rich sequences that are built around tetrads of hydrogen-bonded guanine bases. Accumulating studies have revealed that G-quadruplex structures are formed in vivo and play important roles in biological processes such as DNA replication, transcription, recombination, epigenetic regulation, meiosis, antigenic variation, and maintenance of telomeres stability. Mounting evidence indicates that a variety of proteins are capable of binding selectively and tightly to G-quadruplex and play essential roles in G-quadruplex-mediated regulation processes. Some of these proteins promote the formation or/and stabilization of G-quadruplex, while some other proteins act to unwind G-quadruplex preferentially. From a drug discovery perspective, many of these G-quadruplex binding proteins and/or their complexes with G-quadruplexes are potential drug targets. Here, we present a general summary of reported G-quadruplex binding proteins and their biological functions, with focus on those of medicinal research significance. We elaborated the possibility for some of these G-quadruplex binding proteins and their complexes with G-quadruplexes as potential drug targets.

Background Alzheimer's disease (AD) is a progressive neurodegenerative brain disorder that is characterized by dementia, cognitive impairment, and memory loss. Diverse factors are related to the development of AD, such as increased level of β-amyloid (Aβ), acetylcholine, metal ion deregulation, hyperphosphorylated tau protein, and oxidative stress. Methods The following methods were used: organic syntheses of 1H-phenanthro[9,10-d]imidazole derivatives, inhibition of self-mediated and metal-induced Aβ1–42 aggregation, inhibition studies for acetylcholinesterase and butyrylcholinesterase, anti-oxidation activity studies, CD, MTT assay, transmission electron microscopy, dot plot assay, gel electrophoresis, Western blot, and molecular docking studies. Results We synthesized and characterized a new type of 1H-phenanthro[9,10-d]imidazole derivatives as multifunctional agents for AD treatment. Our results showed that most of these derivatives exhibited strong Aβ aggregation inhibitory activity. Compound 9g had 74% Aβ1–42 aggregation inhibitory effect at 10 μM concentration with its IC50 value of 6.5 μM for self-induced Aβ1–42 aggregation. This compound also showed good inhibition of metal-mediated (Cu2 + and Fe2 +) and acetylcholinesterase-induced Aβ1–42 aggregation, as indicated by using thioflavin T assay, transmission electron microscopy, gel electrophoresis, and Western blot. Besides, compound 9g exhibited cholinesterase inhibitory activity, with its IC50 values of 0.86 μM and 0.51 μM for acetylcholinesterase and butyrylcholinesterase, respectively. In addition, compound 9g showed good anti-oxidation effect with oxygen radical absorbance capacity (ORAC) value of 2.29. Conclusions Compound 9g was found to be a potent multi-target-directed agent for Alzheimer's disease. General significance Compound 9g could become a lead compound for further development as a multi-target-directed agent for AD treatment.

A series of hesperidin derivatives were prepared and identified by IR, (1)H NMR, and MS spectra. These compounds were evaluated in vitro and in vivo based on α-glucosidase inhibition, glucose consumption of HepG2 cells, and blood glucose level in streptozotocin-induced diabetic mice. The results revealed that all the compounds exhibited anti-hyperglycemic activities. The inhibition at 10(-3) M of compounds 3 and 7a on α-glucosidase were 55.02% and 53.34%, respectively, as compared to 54.80% by acarbose. Treated by compound 3 and the reference drug metformin, glucose consumption of HepG2 cell were 1.78 and 2.11 mM, respectively. After the streptozotocin-induced diabetic mice were oral administrated with compound 3 at 100 mg kg(-1) d(-1) for 10 days, the blood glucose level of 3 treated mice (13.23 mM, P

Resistance to RAF-MEK targeted therapy is a major clinical challenge. RAF-MEK inhibitors are initially but only transiently effective in some but not all BRAF mutant patients, and largely ineffective in RAS mutant patients because of resistance. Through a genetic screen in BRAF mutant tumor cells, we show that the Hippo pathway effector YAP acts as a parallel survival input to promote resistance to RAF-MEK inhibitor therapy. Combined YAP and RAF-MEK inhibition was synthetically lethal not only in several BRAF mutant tumor types but also in RAS mutant tumors. Increased YAP in BRAFV600E patient tumors was a biomarker of worse initial response to RAF inhibition in patients, establishing the clinical relevance of our findings. Our data uncover YAP as a novel mechanism of resistance to RAF-MEK targeted therapy. The findings unveil the synthetic lethality of YAP and RAF-MEK co-suppression as a promising strategy to enhance response and patient survival. Citation Format: Luping Lin, Amit Sabnis, Elton Chan, Victor Olivas, Lindsay Cade, Evangelos Pazarentzos, Saurabh Asthana, Dana Neel, Jenny Jiacheng Yan, Xinyuan Lu, Luu Pham, Mingxue Wang, Niki Karachaliou, Maria G. Cao, Jose L. Manzano, Jose L. Ramirez, Jose M. Torres, Fiamma Buttitta, Charles M. Rudin, Eric A. Collisson, Alain Algazi, Eric Robinson, Iman Osman, Eva Munoz-Couselo, Javier Cortes, Dennie T. Frederick, Zachary A. Cooper, Martin McMahon, Antonio Marchetti, Rafael Rosell, Keith T. Flaherty, Jennifer A. Wargo, Trever G. Bivona. The Hippo effector YAP promotes resistance to RAF and MEK targeted therapies. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-239. doi:10.1158/1538-7445.AM2015-LB-239