Reactive oxygen species activated by mitochondria-specific camptothecin prodrug for enhanced chemotherapy

Camptothecin (CPT) has attracted much attention due to its potent antitumor activities. However, the undesirable physicochemical properties, including poor water-solubility, unstable lactone ring and severe adverse effects limit its further application. In this study, two water-soluble prodrugs, CPT-lysine (CPTK) and CPT-arginine (CPTR), were designed and synthesized by conjugating lysine or arginine with CPT, improving its solubility, pharmacokinetic properties and tumor penetration. Importantly, the introduction of arginine into CPTR contributed to the mitochondria-specific delivery, which increased mitochondrial reactive oxygen species (ROS) generation, induced mitochondria dysfunction and enhanced cell apoptosis and in vivo anti-cancer effect. This strategy is believed to hold great potential for organelle-specific synergistic anti-tumor therapy

SIPA1L3 methylation modifies the benefit of smoking cessation on lung adenocarcinoma survival: an epigenomic-smoking interaction analysis

Smoking cessation prolongs survival and decreases mortality of patients with non‐small‐cell lung cancer (NSCLC). In addition, epigenetic alterations of some genes are associated with survival. However, potential interactions between smoking cessation and epigenetics have not been assessed. Here, we conducted an epigenome‐wide interaction analysis between DNA methylation and smoking cessation on NSCLC survival. We used a two‐stage study design to identify DNA methylation-smoking cessation interactions that affect overall survival for early‐stage NSCLC. The discovery phase contained NSCLC patients from Harvard, Spain, Norway, and Sweden. A histology‐stratified Cox proportional hazards model adjusted for age, sex, clinical stage, and study center was used to test DNA methylation-smoking cessation interaction terms. Interactions with false discovery rate‐q ≤ 0.05 were further confirmed in a validation phase using The Cancer Genome Atlas database. Histology‐specific interactions were identified by stratification analysis in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) patients. We identified one CpG probe (cg02268510SIPA1L3) that significantly and exclusively modified the effect of smoking cessation on survival in LUAD patients [hazard ratio (HR)interaction = 1.12; 95% confidence interval (CI): 1.07-1.16; P = 4.30 × 10-7]. Further, the effect of smoking cessation on early‐stage LUAD survival varied across patients with different methylation levels of cg02268510SIPA1L3. Smoking cessation only benefited LUAD patients with low methylation (HR = 0.53; 95% CI: 0.34-0.82; P = 4.61 × 10-3) rather than medium or high methylation (HR = 1.21; 95% CI: 0.86-1.70; P = 0.266) of cg02268510SIPA1L3. Moreover, there was an antagonistic interaction between elevated methylation of cg02268510SIPA1L3 and smoking cessation (HRinteraction = 2.1835; 95% CI: 1.27-3.74; P = 4.46 × 10−3). In summary, smoking cessation benefited survival of LUAD patients with low methylation at cg02268510SIPA1L3. The results have implications for not only smoking cessation after diagnosis, but also possible methylation‐specific drug targeting

Trans-omics biomarker model improves prognostic prediction accuracy for early-stage lung adenocarcinoma

Limited studies have focused on developing prognostic models with trans-omics biomarkers for early-stage lung adenocarcinoma (LUAD). We performed integrative analysis of clinical information, DNA methylation, and gene expression data using 825 early-stage LUAD patients from 5 cohorts. Ranger algorithm was used to screen prognosis-associated biomarkers, which were confirmed with a validation phase. Clinical and biomarker information was fused using an iCluster plus algorithm, which significantly distinguished patients into high- and low-mortality risk groups (Pdiscovery = 0.01 and Pvalidation = 2.71×10-3). Further, potential functional DNA methylation-gene expression-overall survival pathways were evaluated by causal mediation analysis. The effect of DNA methylation level on LUAD survival was significantly mediated through gene expression level. By adding DNA methylation and gene expression biomarkers to a model of only clinical data, the AUCs of the trans-omics model improved by 18.3% (to 87.2%) and 16.4% (to 85.3%) in discovery and validation phases, respectively. Further, concordance index of the nomogram was 0.81 and 0.77 in discovery and validation phases, respectively. Based on systematic review of published literatures, our model was superior to all existing models for early-stage LUAD. In summary, our trans-omics model may help physicians accurately identify patients with high mortality risk

Production and clinical development of nanoparticles for gene delivery

Gene therapy is a promising strategy for specific treatment of numerous gene-associated human diseases by intentionally altering the gene expression in pathological cells. A successful clinical application of gene-based therapy depends on an efficient gene delivery system. Many efforts have been attempted to improve the safety and efficiency of gene-based therapies. Nanoparticles have been proved to be the most promising vehicles for clinical gene therapy due to their tunable size, shape, surface, and biological behaviors. In this review, the clinical development of nanoparticles for gene delivery will be particularly highlighted. Several promising candidates, which are closest to clinical applications, will be briefly reviewed. Then, the recent developments of nanoparticles for clinical gene therapy will be identified and summarized. Finally, the development of nanoparticles for clinical gene delivery in future will be prospected

Research on the coupling mechanism and influencing factors of digital economy and green technology innovation in Chinese urban agglomerations

Abstract This paper examines the coupling coordination degree between digital economy and green technology innovation in 19 urban agglomerations across China from 2011 to 2020. Through the analysis of the coupling coordination degree model, spatial autocorrelation, multi-distance spatial clustering analysis, kernel density analysis and grey correlation model, this study uncovers the mechanism of coupling between digital economy and green technology in Chinese urban agglomerations. Data analysis revealed a significant increase in the coupling coordination between the digital economy and green technology innovation within urban agglomerations. However, there are noticeable spatial imbalances in this trend. Additionally, the multi-distance spatial distance analysis highlights a shift from a random distribution to a clustered distribution of spatial characteristics. The polarization features vary among each urban agglomeration and exhibit a significant positive spatial correlation. Factors such as economic sustainability, creative talent, policy support, digital impetus, and technological support will affect the coupling mechanism of green technology innovation and the digital economy in China's urban agglomerations. Policy recommendations are proposed to foster the development of the digital economy, promote coordinated growth within and beyond urban clusters, and ultimately build a digital ecological civilization that is both green and intelligent

Crystal polymorphism of polylactides and poly(Pro-alt-CO): The metastable beta and gamma phases. Formation of homochiral PLLA phases in the PLLA/PDLA blends

Among the various crystalline phases of polylactides, an elusive orthorhombic gamma phase (¿PLLA) had been obtained so far only by epitaxial crystallization on hexamethylbenzene. A recent work by J. Shao et al. (Macromolecules, 2013, 46, 6933) reports on two “novel modified crystallites” of PLLA obtained “under the confinement of stereocomplex PLLA/PDLA crystallites” produced on cooling blends of PLLA and PDLA from the melt at specific rates. These novel modified crystallites are metastable and transform to the stable aPLLA on heating. Reinterpretation of Shao et al.'s DSC and X-ray data suggests that one novel modified crystallite is the elusive ¿PLLA. The second form could be a disordered hexagonal phase that blends PDLA and PLLA three-fold helices, although the structural evidence is less compelling. In a parallel line of analysis, a crystal modification of the related alternating copolymer of propene and carbon monoxide (poly(Pro-alt-CO)) described as an orthorhombic structure very similar to ¿PLLA by Anokhin et al. (Polymer Science, Ser. A, Vol. 46, No. 1, 2004, pp. 52–60) must be reinterpreted as a trigonal frustrated phase, a phase that has already been observed in single crystals of this polymer.Postprint (published version

Injectable Polypeptide Hydrogel Depots Containing Dual Immune Checkpoint Inhibitors and Doxorubicin for Improved Tumor Immunotherapy and Post-Surgical Tumor Treatment

In this work, we developed a strategy for local chemo-immunotherapy through simultaneous incorporation of dual immune checkpoint blockade (ICB) antibodies, anti-cytotoxic T-lymphocyte-associated protein 4 (aCTLA-4) and anti-programmed cell death protein 1 (aPD-1), and a chemotherapy drug, doxorubicin (Dox), into a thermo-gelling polypeptide hydrogel. The hydrogel encapsulating Dox or IgG model antibody showed sustained release profiles for more than 12 days in vitro, and the drug release and hydrogel degradation were accelerated in the presence of enzymes. In comparison to free drug solutions or hydrogels containing Dox or antibodies only, the Dox/aCTLA-4/aPD-1 co-loaded hydrogel achieved improved tumor suppression efficiency, strengthened antitumor immune response, and prolonged animal survival time after peritumoral injection into mice bearing B16F10 melanoma. Additionally, after injection of Dox/aCTLA-4/aPD-1 co-loaded hydrogel into the surgical site following tumor resection, a significantly enhanced inhibition on tumor reoccurrence was demonstrated. Thus, the polypeptide hydrogel-based chemo-immunotherapy strategy has potential in anti-tumor therapy and the prevention of tumor reoccurrence