Pyrimidine compounds BY4003 and BY4008 inhibit glioblastoma cells growth via modulating JAK3/STAT3 signaling pathway.

Glioblastoma (GBM) is a brain tumor characterized by its aggressive and invasive properties. It is found that STAT3 is abnormally activated in GBM, and inhibiting STAT3 signaling can effectively suppress tumor progression. In this study, novel pyrimidine compounds, BY4003 and BY4008, were synthesized to target the JAK3/STAT3 signaling pathway, and their therapeutic efficacy and mechanisms of action were evaluated and compared with Tofacitinib in U251, A172, LN428 and patient-derived glioblastoma cells. The ADP-Glo™ kinase assay was utilized to assessed the inhibitory effects of BY4003 and BY4008 on JAK3, a crucial member of the JAK family. The results showed that both compounds significantly inhibited JAK3 enzyme activity, with IC50 values in the nanomolar range. The antiproliferative effects of BY4003, BY4008, and Tofacitinib on GBM and patient-derived glioblastoma cells were evaluated by MTT and H&E assays. The impact of BY4003 and BY4008 on GBM cell migration and apoptosis induction was assessed through wound healing, transwell, and TUNEL assays. STAT3-regulated protein expression and relative mRNA levels were analyzed by western blotting, immunocytochemistry, immunofluorescence, and qRT-PCR. It was found that BY4003, BY4008 and Tofacitinib could inhibit U251, A172, LN428 and patient-derived glioblastoma cells growth and proliferation. Results showed decreased expression of STAT3-associated proteins, including p-STAT3, CyclinD1, and Bcl-2, and increased expression of Bax, a pro-apoptotic protein, as well as significant down-regulation of STAT3 and STAT3-related genes. These findings suggested that BY4003 and BY4008 could inhibit GBM growth by suppressing the JAK3/STAT3 signaling pathway, providing valuable insights into the therapeutic development of GBM.

MinerVa: A high performance bioinformatic algorithm for the detection of minimal residual disease in solid tumors / 生物医学工程学杂志

How to improve the performance of circulating tumor DNA (ctDNA) signal acquisition and the accuracy to authenticate ultra low-frequency mutation are major challenges of minimal residual disease (MRD) detection in solid tumors. In this study, we developed a new MRD bioinformatics algorithm, namely multi-variant joint confidence analysis (MinerVa), and tested this algorithm both in contrived ctDNA standards and plasma DNA samples of patients with early non-small cell lung cancer (NSCLC). Our results showed that the specificity of multi-variant tracking of MinerVa algorithm ranged from 99.62% to 99.70%, and when tracking 30 variants, variant signals could be detected as low as 6.3 × 10 -5 variant abundance. Furthermore, in a cohort of 27 NSCLC patients, the specificity of ctDNA-MRD for recurrence monitoring was 100%, and the sensitivity was 78.6%. These findings indicate that the MinerVa algorithm can efficiently capture ctDNA signals in blood samples and exhibit high accuracy in MRD detection.

Progress in Antiviral Fullerene Research.

Unlike traditional small molecule drugs, fullerene is an all-carbon nanomolecule with a spherical cage structure. Fullerene exhibits high levels of antiviral activity, inhibiting virus replication in vitro and in vivo. In this review, we systematically summarize the latest research regarding the different types of fullerenes investigated in antiviral studies. We discuss the unique structural advantage of fullerenes, present diverse modification strategies based on the addition of various functional groups, assess the effect of structural differences on antiviral activity, and describe the possible antiviral mechanism. Finally, we discuss the prospective development of fullerenes as antiviral drugs.

Tailoring Functional Terminals on Solution-Processable Fullerene Electron Transporting Materials for High Performance Perovskite Solar Cells.

Widely known as an excellent electron transporting material (ETM), pristine fullerene C60 plays a critical role in improving the photovoltaic performance of inverted structure perovskite solar cells (PSCs). However, the imperfect perovskite/C60 interface significantly limits the promotion of device performance and stability due to the weak coordination interactions between bare carbon cages and perovskite. Here, we designed and synthesized three functionalized fulleropyrrolidine ETMs (abbreviated as CEP, CEPE, and CECB), each of which was modified with the same primary terminal (cyanoethyl) and various secondary terminals (phenyl, phenethyl, and chlorobutyl). The resulting CECB-based PSC has a power conversion efficiency (PCE) over 19% and exceptional photo-stability over 1800 h. This work provides significant insight into the targeted terminal design of novel fullerene ETMs for efficient and stable PSCs.

Synthesis of Fullerenes from a Nonaromatic Chloroform through a Newly Developed Ultrahigh-Temperature Flash Vacuum Pyrolysis Apparatus.

The flash vacuum pyrolysis (FVP) technique is useful for preparing curved polycyclic aromatic compounds (PAHs) and caged nanocarbon molecules, such as the well-known corannulene and fullerene C60. However, the operating temperature of the traditional FVP apparatus is limited to ~1250 °C, which is not sufficient to overcome the high energy barriers of some reactions. Herein, we report an ultrahigh-temperature FVP (UT-FVP) apparatus with a controllable operating temperature of up to 2500 °C to synthesize fullerene C60 from a nonaromatic single carbon reactant, i.e., chloroform, at 1350 °C or above. Fullerene C60 cannot be obtained from CHCl3 using the traditional FVP apparatus because of the limitation of the reaction temperature. The significant improvements in the UT-FVP apparatus, compared to the traditional FVP apparatus, were the replacement of the quartz tube with a graphite tube and the direct heating of the graphite tube by impedance heating instead of indirect heating of the quartz tube using an electric furnace. Because of the higher temperature range, UT-FVP can not only synthesize fullerene C60 from single carbon nonaromatic reactants but sublimate some high-molecular-weight compounds to synthesize larger curved PAHs in the future.

Mixed Fullerene Electron Transport Layers with Fluorocarbon Chains Assembling on the Surface: A Moisture-Resistant Coverage for Perovskite Solar Cells.

In p-i-n structure perovskite solar cells (PSCs), the most prevalent electron transport layer (ETL), [6, 6]-phenyl-C61-butyric acid methyl ester (PC61BM), acts as both electron extractor and protective coverage to the underlayer perovskite. Notably, multifunctional mixed fullerene ETLs show great potential in further improving both the power conversion efficiency (PCE) and stability of PSCs compared to the single PC61BM ETL. In this work, we reported the mixed fullerene ETLs comprising of PC61BM and its two analogs with different length of fluorocarbon chains, [6, 6]-phenyl-C61-buryric acid 1H,1H-trifluoro-1-ethyl ester (abbreviated, CF3-PC61BM) and [6, 6]-phenyl-C61-buryric acid 1H, 1H-tridecafluoro-1-heptyl ester (abbreviated, C6F13-PC61BM). We obtained excellent PCEs of 18.37% and 17.71% for 1 wt % CF3-PC61BM- and C6F13-PC61BM-based PSCs (1 wt % addition of PC61BM) with CH3NH3PbI3 (MAPbI3) perovskites, respectively. Moreover, champion PCEs of ∼19% were obtained based on the CsFAMAPbIBr perovskites. Subsequent experiments demonstrated that the fluorocarbon chains of CF3-PC61BM and C6F13-PC61BM assembled at the surfaces of ETLs with the formation of thin-layer moisture-resistant protective coverage above perovskite. Results show that it significantly retarded water penetrating down to perovskite layers and led to optimal humidity stability under ambient atmosphere.

Defining Treatment Response, Remission, Relapse, and Recovery in First-Episode Psychosis: A Survey among Korean Experts.

OBJECTIVE: For the proper treatment of first-episode psychosis, assessment of treatment response, remission, relapse, and recovery is important. Therefore, the present study aimed to develop operational definitions of clinical outcomes in first-episode psychosis. METHODS: A questionnaire was developed by a panel of experts and underwent three revisions. The final survey was presented to 150 psychiatrists who were members of the Korean Society for Schizophrenia Research. Respondents selected factors that they believed were important to consider while defining treatment response, remission, relapse, and recovery using a 6-point Likert scale. Selected factors that constituted each definition were statistically extracted, and operational definitions were developed. RESULTS: A total of 91 experts responded to the survey. The extent of reduction in psychopathology, socio-occupational functioning, and duration of each state were the core factors of each definition. Outcomes obtained from discussions and consultations by experts have been summarized and proposed. CONCLUSION: The criteria developed in this survey tended to be somewhat stricter than those used by other studies. The fundamental reason for this is that this survey focused on first-episode psychosis. A better understanding of each definition in first-episode psychosis is necessary to improve effective treatment outcomes.

Rational synthesis of an atomically precise carboncone under mild conditions.

Carboncones, a special family of all-carbon allotropes, are predicted to have unique properties that distinguish them from fullerenes, carbon nanotubes, and graphenes. Owing to the absence of methods to synthesize atomically well-defined carboncones, however, experimental insight into the nature of pure carboncones has been inaccessible. Herein, we describe a facile synthesis of an atomically well-defined carboncone[1,2] (C70H20) and its soluble penta-mesityl derivative. Identified by x-ray crystallography, the carbon skeleton is a carboncone with the largest possible apex angle. Much of the structural strain is overcome in the final step of converting the bowl-shaped precursor into the rigid carboncone under mild reaction conditions. This work provides a research opportunity for investigations of atomically precise single-layered carboncones having even higher cone walls and/or smaller apex angles.

A Nanoparticle-Decorated Biomolecule-Responsive Polymer Enables Robust Signaling Cascade for Biosensing.

To meet the increasing demands for ultrasensitivity in monitoring trace amounts of low-abundance early biomarkers or environmental toxins, the development of a robust sensing system is urgently needed. Here, a novel signal cascade strategy is reported via an ultrasensitive polymeric sensing system (UPSS) composed of gold nanoparticle (gNP)-decorated polymer, which enables gNP aggregation in polymeric network and electrical conductance change upon specific aptamer-based biomolecular recognition. Ultralow concentrations of thrombin (10-18 m) as well as a low molecular weight anatoxin (165 Da, 10-14 m) are detected selectively and reproducibly. The biomolecular recognition induced polymeric network shrinkage responses as well as dose-dependent responses of the UPSS are validated using in situ real-time atomic-force microscopy, representing the first instance of real-time detection of biomolecular binding-induced polymer shrinkage in soft matter. Furthermore, in situ real-time confocal laser scanning microscopy imaging reveals the dynamic process of gNP aggregation responses upon biomolecular binding.

A Hydrogel-Based Hybrid Theranostic Contact Lens for Fungal Keratitis.

Fungal keratitis, a severe ocular disease, is one of the leading causes of ocular morbidity and blindness, yet it is often neglected, especially in developing countries. Therapeutic efficacy of traditional treatment such as eye drops is very limited due to poor bioavailability, whereas intraocular injection might cause serious side effects. Herein, we designed and fabricated a hybrid hydrogel-based contact lens which comprises quaternized chitosan (HTCC), silver nanoparticles, and graphene oxide (GO) with a combination of antibacterial and antifungal functions. The hydrogel is cross-linked through electrostatic interactions between GO and HTCC, resulting in strong mechanical properties. Voriconazole (Vor), an antifungal drug, can be loaded onto GO which retains the drug and promotes its sustained release from the hydrogel-based contact lenses. The contact lenses also exhibited good antimicrobial functions in view of glycidyltrimethylammonium chloride and silver nanoparticles. The results from in vitro and in vivo experiments demonstrate that contact lenses loaded with Vor have excellent efficacy in antifungal activity in vitro and could significantly enhance the therapeutic effects on a fungus-infected mouse model. The results indicate that this hydrogel contact lenses-based drug delivery system might be a promising therapeutic approach for a rapid and effective treatment of fungal keratitis.

Floatable, macroporous structured alginate sphere supporting iron nanoparticles used for emergent Cr(VI) spill treatment.

Treatment of hexavalent chromium (Cr(VI)) spill accident is a great challenge due to its high toxicity, sudden and extensiveness. In this study, we designed and fabricated a hierarchical, ordered and macroporous structured alginate sphere to support in-situ synthesized zero-valent iron nanoparticle (the alginate-nZVI sphere). Field emission scanning electron microscope (FESEM) and energy-dispersive X-ray spectroscopy (EDS) images showed well dispersion of nZVI on the composite. This alginate-nZVI sphere exhibited good separability in effective removal of Cr(VI). The result from Cr(VI) removal experiment demonstrated a Cr(VI) removal efficiency of 98.2% at equilibrium time, which can be ascribed to the well dispersion of the nZVI. In addition, the alginate-nZVI sphere was effective in Cr(VI) removal in a wide range of pH from 3.0 to 11.0, by the merit of alginate substrate. Hence, the alginate-nZVI sphere might be a promising agent for an emergent Cr(VI) spill treatment by enhancing the dispersion, stabilization and separation properties of nZVI.

The synthesis of puerarin derivatives and their protective effect on the myocardial ischemia and reperfusion injury.

Puerarin is a naturally occurring isoflavone and is frequently used for the treatment of cardiovascular symptoms in China. By the structural modification of the puerarin molecule at different positions, seven new puerarin derivatives were obtained, and their cardioprotective activities (in vitro and in vivo) were respectively evaluated. The finding that the activities of 3 and 8 markedly exceeded puerarin suggested that the acylated modification of phenolic hydroxyl at C-7 in the puerarin molecule may improve the cardioprotective activity, which will be an important reference for further structural optimization.

[Synthesis and antitumor activity of 20-O-linked camptothecin ester derivatives].

AIM: To improve the profile of 20 (S)-camptothecin, a series of 20-O-linked camptothecin phenoxyacetic acid ester derivatives have been designed. METHODS: These derivatives were synthesized by the method of acylation. Their chemical structures were confirmed with 1HNMR, IR, MS, and HRMS. The cytotoxicities of the compounds were tested by MTT assay. The in vivo antitumor activities of these esters were evaluated against mouse liver tumor H22 in mice. RESULTS: Twelve derivatives of camptothecin ester are new compounds. CONCLUSION: In vitro and in vivo antitumor activity has indicated that some derivatives appeared significantly more effective than topotecan in the H22 mouse liver tumoral model.

Synthesis and antitumor activity of 20-O-linked camptothecin ester derivatives / 药学学报

<p><b>AIM</b>To improve the profile of 20 (S)-camptothecin, a series of 20-O-linked camptothecin phenoxyacetic acid ester derivatives have been designed.</p><p><b>METHODS</b>These derivatives were synthesized by the method of acylation. Their chemical structures were confirmed with 1HNMR, IR, MS, and HRMS. The cytotoxicities of the compounds were tested by MTT assay. The in vivo antitumor activities of these esters were evaluated against mouse liver tumor H22 in mice.</p><p><b>RESULTS</b>Twelve derivatives of camptothecin ester are new compounds.</p><p><b>CONCLUSION</b>In vitro and in vivo antitumor activity has indicated that some derivatives appeared significantly more effective than topotecan in the H22 mouse liver tumoral model.</p>

Regioselective synthesis and cytotoxicities of camptothecin derivatives modified at the 7-, 10- and 20-positions.

A series of 7-acyloxymethylcamptothecin and 20-O-acyl-7-acyloxymethylcamptothecin derivatives were regioselectively prepared on different solvents. 7-Acyloxymethylcamptothecins possess more efficacy than 20-O-acyl-7-acyloxymethylcamptothecins against six human cancer cell lines in vitro.