Development of a novel sialic acid-conjugated camptothecin prodrug for enhanced cancer chemotherapy.

Camptothecin (CPT) is an attractive natural drug for cancer chemotherapy. However, the poor water solubility, non-targeting feature, and adverse side effects of CPT are significant obstacles to developing an effective anticancer drug. Here, for the first time, 9-thiol-sialic acid (9-SH-Sia) is coupled to CPT by forming a disulfide releasable carbonate linkage, resulting in a novel CPT prodrug (CPT-ss-Sia) that self-assembles into nanostructures in an aqueous solution. Strikingly, CPT-ss-Sia exhibited excellent in vitro properties, including enhanced water solubility, glutathione (GSH)-triggered CPT release, and increased E-lactone ring stability. Furthermore, CPT-ss-Sia had good cancer cell-killing ability comparable to CPT. Intravenous administration of CPT-ss-Sia significantly inhibited the growth of multiple types of tumors. Histological analysis showed that CPT-ss-Sia treatment significantly reduced lesions in tumor-bearing mice compared to CPT treatment. Notably, CPT-ss-Sia treatment did not adversely affect the body weight of the mice. This is the first report of the 9-SH-Sia conjugate-based prodrug. Overall, CPT-ss-Sia has broad clinical application prospects.

miR-140-3P Induces Chemotherapy Resistance in Esophageal Carcinoma by Targeting the NFYA-MDR1 Axis.

Esophageal carcinoma (EC) is recognized as the 6th most frequent carcinoma in China, with esophageal squamous cell carcinoma (ESCC) being the predominant histologic type. Currently, chemotherapy is one among the most important therapy modalities for patients with ESCC. However, resistance to chemotherapeutic drugs leads to limited treatment options and poor prognosis. In our study, the analysis of small RNA sequencing and digital gene expression (DGE) profiling was done to recognize the microRNAs (miRNAs) and key genes related with drug resistance in ESCC. It was noticed that the hsa-miRNA-140-3p (miR-140-3p) expression was considerably higher in drug-resistant cells than in sensitive cells. In addition, DGE identified target genes of miR-140-3p might perform key roles in ESCC. Furthermore, this work exhibited that miR-140-3p represents the nuclear transcription factor Y subunit alpha (NFYA) gene by targeting its 3'-untranslated regions. Such an interaction might influence the formation of the transcription factor NFY trimer, which in turn may inhibit the transcription of the multidrug resistance 1 gene and, ultimately, to multidrug resistance in ESCC. The inhibition of miR-140-3p decreased resistance to oxaliplatin in EC. Therefore, miR-140-3p may serve as a molecular marker for treatment response, efficacy, and prognosis of chemotherapy in ESCC patients.

Synthesis of sialic acid conjugates of the clinical near-infrared dye as next-generation theranostics for cancer phototherapy.

Cancer is a multifaceted global health problem that requires continuous action to develop next-generation cancer theranostics. Inspired by the emerging use of indocyanine green (ICG), the only clinically approved near-infrared (NIR) dye for cancer phototherapy, here we synthesized two ICG conjugate theranostics by coupling ICG to sialic acid (Sia) through the C2 and C9 positions of Sia, respectively, referred to as Sia-C2-ICG and Sia-C9-ICG. Encouragingly, Sia-C2/C9-ICGs show superior in vitro properties, including enhanced stability, reduced non-specific binding to serum proteins, and improved blood compatibility, highlighting the benefits of Sia coupling. Notably, in vivo NIR imaging shows that Sia-C9-ICG significantly promotes tumor targeting and effectively prolongs the circulation time in the body, while Sia-C2-ICG is superior to ICG but inferior to Sia-C9-ICG in targeting tumors. Furthermore, Sia-C9-ICG combined with NIR laser irradiation can lead to excellent photothermal and photodynamic therapies for cancer cells, resulting in superior solid tumor ablation. To our knowledge, this is the first report of Sia-NIR conjugates achieving significant tumor reduction in vivo. Together, these advances render Sia-C9-ICG an attractive lead as next-generation cancer theranostics that can be translated clinically to treat human patients.

Palbociclib Enhances Migration and Invasion of Cancer Cells via Senescence-Associated Secretory Phenotype-Related CCL5 in Non-Small-Cell Lung Cancer.

Palbociclib is the first CDK4/6 inhibitor approved by FDA and has been studied in many types of cancer. However, some studies showed that it could induce epithelial-mesenchymal transition (EMT) of cancer cells. To test the effect of palbociclib on non-small-cell lung cancer (NSCLC) cells, we treated NSCLC cells with different concentrations of palbociclib and detected its effects via MTT, migration and invasion assays, and apoptosis test. Further RNA sequencing was performed in the cells treated with 2 µM palbociclib or control. And Gene Ontology, Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Set Enrichment Analysis (GSEA), and protein-protein interaction network (PPI) were analyzed to explore the mechanism of palbociclib. The results showed that palbociclib significantly inhibited the growth of NSCLC cells and promoted apoptosis of cells, however, enhanced the migration and invasion abilities of cancer cells. RNA sequencing showed that cell cycle, inflammation-/immunity-related signaling, cytokine-cytokine receptor interaction, and cell senescence pathways were involved in the process, and CCL5 was one of the significantly differential genes affected by palbociclib. Further experiments showed that blocking CCL5-related pathways could reverse the malignant phenotype induced by palbociclib. Our results revealed that palbociclib-induced invasion and migration might be due to senescence-associated secretory phenotype (SASP) rather than EMT and suggested that SASP could act as a potential target to potentiate the antitumor effects of palbociclib in cancer treatment.

Atypical Response in Metastatic Non-Small Cell Lung Cancer Treated with PD-1/PD-L1 Inhibitors: Radiographic Patterns and Clinical Value of Local Therapy.

PURPOSE: To explore the clinical characteristics, management, and survival outcomes of advanced NSCLC patients treated with PD-1/PD-L1 inhibitors who presented with an atypical response (AR). METHODS: A total of 926 PD-1/PD-L1-inhibitor-treated patients with metastatic NSCLC from three academic centers were retrospectively reviewed. All measurable lesions were evaluated by RECIST version 1.1. RESULTS: Fifty-six (6.1%) patients developed AR. The median time to the occurrence of AR was 2.0 months. Patients with no fewer than 3 metastatic organs at baseline were more prone to develop AR in advanced NSCLC (p = 0.038). The common sites of progressive lesions were lymph nodes (33.8%) and lungs (29.7%). The majority (78.2%) of patients with AR had only 1-2 progressive tumor lesions, and most (89.1%) of the progressive lesions developed from originally existing tumor sites. There was no significance in terms of survival between patients with AR and those with typical response (TR). Local therapy was an independent predictor for PFS of patients with AR (p = 0.025). CONCLUSIONS: AR was not an uncommon event in patients with metastatic NSCLC treated with PD-1/PD-L1 inhibitors, and it had a comparable prognosis to those with TR. Proper local therapy targeting progressive lesions without discontinuing original PD-1/PD-L1 inhibitors may improve patient survival.

Developing Acid-Responsive Glyco-Nanoplatform Based Vaccines for Enhanced Cytotoxic T-lymphocyte Responses Against Cancer and SARS-CoV-2.

Cytotoxic T-lymphocytes (CTLs) are central for eliciting protective immunity against malignancies and infectious diseases. Here, for the first time, partially oxidized acetalated dextran nanoparticles (Ox-AcDEX NPs) with an average diameter of 100 nm are fabricated as a general platform for vaccine delivery. To develop effective anticancer vaccines, Ox-AcDEX NPs are conjugated with a representative CTL peptide epitope (CTLp) from human mucin-1 (MUC1) with the sequence of TSAPDTRPAP (referred to as Mp1) and an immune-enhancing adjuvant R837 (referred to as R) via imine bond formation affording AcDEX-(imine)-Mp1-R NPs. Administration of AcDEX-(imine)-Mp1-R NPs results in robust and long-lasting anti-MUC1 CTL immune responses, which provides mice with superior protection from the tumor. To verify its universality, this nanoplatform is also exploited to deliver epitopes from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to prevent coronavirus disease 2019 (COVID-19). By conjugating Ox-AcDEX NPs with the potential CTL epitope of SARS-CoV-2 (referred to as Sp) and R837, AcDEX-(imine)-Sp-R NPs are fabricated for anti-SARS-CoV-2 vaccine candidates. Several epitopes potentially contributing to the induction of potent and protective anti-SARS-CoV-2 CTL responses are examined and discussed. Collectively, these findings shed light on the universal use of Ox-AcDEX NPs to deliver both tumor-associated and virus-associated epitopes.

Multi-State Analysis of the Impact of Childhood Starvation on the Healthy Life Expectancy of the Elderly in China.

Background: Child malnutrition is not only common in developing countries but also an important issue faced by developed countries. This study aimed to explore the influence and degree of childhood starvation on the health of the elderly, which provides a reference for formulating health-related policies under the concept of full lifecycle health. Methods: Based on the Chinese Longitudinal Healthy Longevity Survey (CLHLS) in 2008, 2011, and 2014, this study took a total of 13,185 elderly people aged 65-99 years as the target population. By IMaCH software, with gender and income level as the control variables, the average life expectancy and healthy life expectancy of the elderly were measured. The x2test was used to explore the differences in the socioeconomic status of elderly people with or without starvation in childhood. Statistical differences between average life expectancy and healthy life expectancy were analyzed by rank tests. Results: (1) The results showed that there was a statistically significant difference in age, gender, residency, education level, and income level between the groups with or without starvation (P < 0.05). (2) Transition probabilities in health-disability, health-death, and disability-death all showed an upward trend with age (P < 0.05), where the elderly who experienced starvation in childhood were higher than those without such an experience (P < 0.05). However, the probability of disability-health recovery showed a downward trend with age (P < 0.05), in which the elderly who experienced starvation in childhood were lower than those without starvation (P < 0.05). (3) For the elderly who experienced starvation in childhood, the health indicators of the average life expectancy, healthy life expectancy, and healthy life expectancy proportion accounted for the remaining life were lower than those of the elderly without childhood starvation (P < 0.05). Conclusions: The average life expectancy and healthy life expectancy of the elderly with childhood starvation are lower than those without childhood starvation. It shows that the negative impact of childhood starvation on health through the life course till old age has a persistent negative cumulative effect on the quantity and quality of life. Therefore, it is important to pay attention to the nutritional status of children in poor families from the perspective of social policymaking.

A comparative analysis on risk communication between international and Chinese literature from the perspective of knowledge domain visualization.

BACKGROUND: The outbreak of coronavirus disease (COVID-19) severely damaged and endangered people's lives at the end of 2019. Risk communication plays an important role in the response to it successfully, which has been appreciated by the World Health Organization. Therefore, a comprehensive analysis of risk communication research is necessary, which can understand current research hotspots and reveal new trends. METHODS: In this study, we collected 1134 international articles from the Web of Science database and 3983 Chinese articles from the China National Knowledge Infrastructure database. Bibliometric and mapping knowledge domain analysis methods were used for temporal distribution analysis, cooperation network analysis, co-word network analysis, and burst detection analysis. RESULTS: The first article in this field was published by western scholars earlier, while the first Chinese article in 2002. Research institutions mainly come from universities. The USA plays a key role in this field. Chinese scholars had a closer cooperation network, but there was less cooperation among domestic institutions. Risk perception, trust, risk management, and risk information had always been the research hotspots in this academic. Trust, sentiment research, and public risk events were essential directions for the future. There are 25 burst words for international articles, while 11 burst words for Chinese articles from 2000 to 2020. CONCLUSIONS: In summary, both domestic and international researchers are concerned about risk communication, risk perception, trust, and risk information. International research on risk communication is systematic and comprehensive relatively. However, Chinese scholars take severe acute respiratory syndrome as the research background and reviewing foreign knowledge as the research starting point. With the purpose of practical and applied research based on a public emergency, the risk communication research lacks continuity in Chinese academy in the past years.

Using Cellulose Nanocrystal as Adjuvant to Improve the Dispersion Ability of Multilayer Graphene in Aqueous Suspension.

Cellulose nanocrystal (CNC) has been applied in various fields due to its nano-structure, high aspect ratio, specific surface area and modulus, and abundance of hydroxy groups. In this work, CNC suspensions with different concentrations (0.4, 0.6, and 0.8%) were used as the adjuvant to improve the dispersion ability of multilayer graphene (MLG) in aqueous suspension, which is easy to be aggregated by van der Waals force between layers. In addition, N-methyl-2-pyrrolidone, ethanol, and ultrapure water were used as control groups. Zeta potential analysis and Fourier transform infrared spectroscopy showed that the stability of MLG/CNC has met the requirement, and the combination of CNC and MLG was stable in aqueous suspension. Results from transmission electron microscopy, Fourier transform infrared spectroscopy, and absorbance showed that MLG had a better dispersion performance in CNC suspensions, compared to the other solutions. Raman spectrum analysis showed that the mixtures of 1.0 wt% MLG with 0.4% CNC had the least defects and fewer layers of MLG. In addition, it is found that CNC suspension with 0.8% concentration showed the highest ability to disperse 1.0 wt% MLG with the most stable performance in suspension. Overall, this work proved the potential application of CNC as adjuvant in the field of graphene nanomaterials.

Coupling Biocompatible Au Nanoclusters and Cellulose Nanofibrils to Prepare the Antibacterial Nanocomposite Films.

Cellulose nanofibrils (CNF) is considered as an inexhaustible precursor to produce antibacterial materials, such as antibacterial hydrogel, antibacterial paper, and antibacterial film. However, the poor antimicrobial property of neat CNF required it should be coupled with an antibacterial ingredient. Herein, biocompatible Au nanoclusters (AuNCs) were synthesized and added into the CNF dispersion to prepare a novel antibacterial film (AuNCs@CNF film). The effects of addition of AuNCs with different amount on the morphology and physicochemical properties of AuNCs@CNF films were characterized using atomic force microscopy (AFM), scanning electron microscopy (SEM), X-ray diffraction (XRD), FTIR (Fourier-transform infrared), light transmittance spectra, and thermogravimetric analysis (TGA). The results showed that AuNCs did not affect the nano-structural features of the CNF film and its basic structures, but could greatly increase the hydrophilicity, the flexibility and the thermal stability of CNF film, which might improve its application in antimicrobial wound-healing dressing. The prepared AuNCs@CNF films demonstrated high antibacterial properties toward Escherichia coli (E. coli) and Streptococcus mutans (S. mutans) both in vitro and in vivo, which can prohibit their growths and promote the healing of bacteria-infected wound, respectively. Thus, the prepared AuNCs@CNF film with great antibacterial properties could be applicable in biomedical field.

Isolation of the Flavonoid from Bamboo Residues and Its Application as Metal Ion Sensor in Vitro.

Fluorescence sensors prepared from natural polymers have received increasing attention based on their luminescence characteristics for bioimaging, cell imaging, and intracellular detection of inorganic metabolites. In this work, flavonoids isolated from bamboo residues (BRF) were applied as fluorescence sensors for different metal cations' detection in vitro. Results showed the optimal flavonoids extraction condition of solid to liquid ratio, ethanol concentration, extraction time and temperature were determined at 1:25, 50%, 240 min and 90 °C, respectively, resulting in an extraction yield with 104.7 mg/100 g bamboo residues. The BRF is mainly composed of isoorientin, isovitexin, pinosylvin, tricin and isorhamnetin by liquid chromatography-mass spectrometry (LC-MS) analysis. It is found that the BRF displayed strong blue-green emission as well as notable excitation, which can selectively and sensitively detect Fe3+ with the limit of detection (LOD) as low as 38.0 nM. In the Fe3+ detection was no obvious interference by other cations except for Al3+. In addition, the BRF displayed excellent biocompatibility that can be applied to bioimages of the intracellular detection of Fe3+ in L02 cells. Finally, it is found that the BRF possessed significant antioxidant properties in scavenging H2O2-induced endogenous reactive oxygen species (ROS) in a zebrafish module (in vivo) and L02 cells (in vitro). These results showed that the flavonoid products sustainably isolated from an abundant lignocellulosic waste appear to be effective fluorescent sensors for Fe3+ detection in biological systems with excellent biocompatibility and antioxidant activity.

Synthesis of Carbon Quantum Dot Nanoparticles Derived from Byproducts in Bio-Refinery Process for Cell Imaging and In Vivo Bioimaging.

The carbon quantum dot (CQD), a fluorescent carbon nanoparticle, has attracted considerable interest due to its photoluminescent property and promising applications in cell imaging and bioimaging. In this work, biocompatible, photostable, and sustainably sourced CQDs were synthesized from byproducts derived from a biorefinery process using one-pot hydrothermal treatment. The main components of byproducts were the degradation products (autohydrolyzate) of biomass pretreated by autohydrolysis. The as-synthesized CQDs had a size distribution from 2.0⁻6.0 nm and had high percentage of sp² and sp³ carbon groups. The CQDs showed blue-green fluorescence with a quantum yield of ~13%, and the fluorescence behaviors were found to be stable with strong resistance to photobleaching and temperature change. In addition, it is found that the as-synthesized CQDs could be used for imaging of cells and tumors, which show potential applications in bioimaging and related fields such as phototherapy and imaging.

Pore structure and pertinent physical properties of nanofibrillated cellulose (NFC)-based foam materials.

Nanofibrillated cellulose (NFC)-based foam materials have broad prospects in replacing traditional foams, due to its facile natural biodegradation. This study addressed the relationship between the foam preparation process parameters and resulting pore structure. An aqueous NFC suspension was freeze-dried while adding an organic solvent, ethanol, to adjust the curing process. The effects of the solid content and freeze-drying temperature on the microstructure and mechanical stability as well as heat transfer performance of the produced NFC-based foam were investigated. The foam obtained at a 3%-5% solid content featured a well-defined lamellar and interlayer pillar support structure. With an increase in the solid content, the average wall thickness increased whereas the average pore area decreased. Yet the pore density increased with the pore distribution becoming non-uniform. With a decrease in freezing temperature, the wall thickness decreased (with no wall structure at -196 °C) but the pore density increased, with the pores being distributed more uniformly. The foam mechanical strength and thermal conductivity were found to be linked to porosity. The foam material had the most suitable mechanical and thermal insulation properties when prepared with a 5% solid content at a freeze-drying temperature of -55 °C.

Differences in gut microbiota between silkworms (Bombyx mori) reared on fresh mulberry (Morus alba var. multicaulis) leaves or an artificial diet.

Artificial diets for silkworms have many potential applications and they are important in sericulture. However, the challenges of weak larvae and low silk protein synthesis efficiency in silkworms reared on artificial diets have not been resolved. Here, we used high-throughput sequencing to analyse the differences between the gut microbiota of 5th-instar larvae reared on mulberry leaves and larvae reared on an artificial diet. The results showed that at the phylum level, Cyanobacteria, Firmicutes, Proteobacteria, Bacteroidetes and Actinobacteria are the dominant bacteria in the intestines of silkworm larvae of all the strains. But the abundance of dominant bacteria in the gut microbiota differed between the silkworm strains that were reared on mulberry leaves, as well as between the silkworm strains that were reared on the artificial diet, while the gut microbiota diversity was lower in the silkworm strains that were reared on the artificial diet. Prediction of the functions of the gut microbiota in the hosts indicated that there was no significant difference between the silkworm strains that were reared on mulberry leaves, while there were significant differences between silkworm strains reared on the artificial diet. When the silkworm diet changed from mulberry leaves to the artificial diet, changes in gut microbiota in the silkworms affected host nutrient metabolism and immune resistance. These changes may be related to the adaptation of silkworms to their long evolutionary history of eating mulberry leaves.

Metabolomics differences between silkworms (Bombyx mori) reared on fresh mulberry (Morus) leaves or artificial diets.

Silkworms (Bombyx mori) reared on artificial diets have great potential applications in sericulture. However, the mechanisms underlying the enhancement of metabolic utilization by altering silkworm nutrition are unclear. The aim of this study was to investigate the mechanisms responsible for the poor development and low silk protein synthesis efficiency of silkworms fed artificial diets. After multi-generational selection of the ingestive behavior of silkworms to artificial diets, we obtained two strains, one of which developed well and another in which almost all its larvae starved to death on the artificial diets. Subsequently, we analyzed the metabolomics of larval hemolymph by gas chromatography/liquid chromatography-mass spectrometry, and the results showed that vitamins were in critically short supply, whereas the nitrogen metabolic end product of urea and uric acid were enriched substantially, in the hemolymph of the silkworms reared on the artificial diets. Meanwhile, amino acid metabolic disorders, as well as downregulation of carbohydrate metabolism, energy metabolism, and lipid metabolism, co-occurred. Furthermore, 10 male-dominant metabolites and 27 diet-related metabolites that differed between male and female silkworms were identified. These findings provide important insights into the regulation of silkworm metabolism and silk protein synthesis when silkworms adapt to an artificial diet.