The timing of durvalumab administration affects the risk of pneumonitis in patients with locally advanced non-small cell lung cancer: a systematic review and meta-analysis.

PURPOSE: The PACIFIC study has demonstrated that the administration of durvalumab following concurrent chemoradiotherapy can significantly improve both overall survival and progression-free survival rates in patients with locally advanced unresectable non-small cell lung cancer. While the latest NCCN guidelines recommend this combination regimen, they do not specify the optimal timing for administering durvalumab after completing radiotherapy. The PACIFIC study suggested initiating durvalumab within 42 days of completing radiotherapy, but early administration of the drug may increase the incidence of pneumonitis. Therefore, we conducted this study to investigate whether the time interval between completion of radiotherapy and initiation of durvalumab treatment is associated with the risk of pneumonitis (Grade ≥ 3), which is the primary endpoint, as well as progression-free survival, which is the secondary endpoint. METHODS: A comprehensive search of clinical trials in PubMed and EMBASE was conducted up to March 2023 to identify clinical trials involving locally advanced unresectable non-small cell lung cancer patients who were treated with durvalumab following chemoradiotherapy. Meta-analysis was performed on single-arm studies to estimate the incidence of pneumonitis (Grade ≥ 3) and progression-free survival in all studies, as well as in studies that administered durvalumab within 42 days after completion of radiotherapy. RESULTS: This meta-analysis consisted of nine studies with a total of 2560 patients. The analysis showed that the incidence of pneumonitis (Grade ≥ 3) was 5.36% [95%CI (0.03, 0.08), I2 = 18.41%, p = 0.29], while the 1-year progression-free survival rate was 57.91% [95%CI (0.53, 0.63), I2 = 10.57%, p = 0.35]. Furthermore, when the duration between completion of radiotherapy and initiation of durvalumab treatment was shorter than 42 days, the incidence of pneumonitis (Grade ≥ 3) was 4.12% [95%CI (0.02, 0.06), I2 = 0.00%, p = 0.56], with a 1-year progression-free survival rate of 61.03% [95%CI (0.51, 0.71), I2 = 59.06%, p = 0.09]. CONCLUSION: Overall, based on the available evidence, it appears that there is no significant increase in pneumonitis or decrease in progression-free survival (PFS) when the time interval is less than 42 days and a shorter interval between treatment sessions does not necessarily have a detrimental effect on the rate of pneumonitis. We recommend that clinicians carefully evaluate the specific circumstances of each patient to determine the optimal timing for initiating immunotherapy.

The emerging role of exosomes in radiotherapy.

Presently, more than half of cancer patients receive radiotherapy to cure localized cancer, palliate symptoms, or control the progression of cancer. However, radioresistance and radiation-induced bystander effects (RIBEs) are still challenging problems in cancer treatment. Exosomes, as a kind of extracellular vesicle, have a significant function in mediating and regulating intercellular signaling pathways. An increasing number of studies have shown that radiotherapy can increase exosome secretion and alter exosome cargo. Furthermore, radiation-induced exosomes are involved in the mechanism of radioresistance and RIBEs. Therefore, exosomes hold great promise for clinical application in radiotherapy. In this review, we not only focus on the influence of radiation on exosome biogenesis, secretion and cargoes but also on the mechanism of radiation-induced exosomes in radioresistance and RIBEs, which may expand our insight into the cooperative function of exosomes in radiotherapy. Video abstract.

Retraction Note: Chondro-protective effects of polydatin in osteoarthritis through its effect on restoring dysregulated autophagy via modulating MAPK, and PI3K/Akt signaling pathways.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Chondroprotective and antiarthritic effects of Daphnetin used in vitro and in vivo osteoarthritis models.

AIMS: Daphnetin (DAP) is a traditional Chinese drug usually used to treat cardiovascular diseases. Studies have confirmed the anti-inflammatory, antioxidant, anti-bacterial and insecticidal, anti-tumor and neuro-protective effects of DAP. However, its anti-arthritic potential remains unexplored. The aim of this study is to investigate the in vitro and in vivo chondroprotective effects of DAP. MAIN METHODS: The effect of DAP on primary rabbit chondrocytes was examined using recombinant human IL-1ß for 24 h. For the in vivo studies, rabbits were randomly divided into groups: a normal control group and osteoarthritis (OA) groups. The OA groups received three different doses of DAP for 4 or 8 weeks. The anti-arthritic effect of DAP was assessed using histopathological examinations, qRT-PCR, western blotting and immunohistochemical analysis. KEY FINDINGS: Both in vitro and in vivo results indicate that DAP exerts a protective effect against IL-1ß in chondrocytes. In vitro, DAP inhibits the expression of IL-6, IL-12, MMP-3, MMP-9 and MMP-13, induced by IL-1ß in rabbit chondrocytes, and stimulates the production of IL-10. The inhibitory effect of DAP on the MMPs is partially regulated by the inhibition of the PI3K/AKT, MAPK and NF-κB signaling pathways. The effect of DAP on OA may be attributed to the suppression of inflammatory factor secretion, chondrocyte apoptosis observed by the decrease in pro-apoptotic Caspase-3 and BAX, and the activation of anti-apoptotic BCL-2. SIGNIFICANCE: DAP has a broad range of prospects in the treatment of OA, which provides a novel therapeutic strategy for OA.

Gö6983 attenuates breast cancer-induced osteolysis by the apoptotic pathway.

Bone metastasis caused by breast cancer leads to significant complications in treatment, and the resulting osteolysis considerably affects patients' overall survival and quality of life. Gö6983 is a broad spectrum protein kinase C inhibitor. In this study, based on our finding that the Gö6983 inhibits osteolysis, we applied Gö6983 to the MDA-MB-231 breast cancer-induced mouse bone metastasis model. And we found that Gö6983 has a strong inhibitory effect on the tumorigenic model of breast cancer by promoting the mitochondrial apoptosis pathway. Our study, therefore, demonstrates that Gö6983 has a potential inhibitory effect on breast cancer-induced osteoclast activation and provides mechanistic insight that may prove useful for designing future treatments.

Chondro-protective effects of polydatin in osteoarthritis through its effect on restoring dysregulated autophagy via modulating MAPK, and PI3K/Akt signaling pathways.

Osteoarthritis (OA) is a degenerative disease of the cartilage that is prevalent in the middle-aged and elderly demography. Polydatin (PD), a natural resveratrol glucoside, has shown significant anti-inflammatory and anti-arthritic potential in previous studies. This study was designed to evaluate the therapeutic properties of PD in vitro and in vivo, and elucidate their underlying mechanisms. The expression levels of all relevant factors were evaluated by qRT-PCR, western blotting, and immunohistochemistry (IHC) where suitable. Reactive oxygen species (ROS) and apoptosis were analyzed using the suitable probes and flow cytometry. The histological evidence of cartilage was assessed in rat models, moreover, the several serum cytokines levels and autophagy levels were evaluated. The result showed PD displayed significant chondro-protective effects, inferred in terms of reduced inflammation and cartilage degradation, apoptosis inhibition, and lower ROS production. The protective effects were attenuated by the autophagy inhibitor 3-MA, indicating a mediating role of autophagy in PD action. Mechanistically, PD exerted its effects by inhibiting the MAPK and PI3K/Akt signaling pathways which led to the down-regulation of mTOR. In conclusion, PD protects against cartilage degeneration by activating the autophagy flux in the chondrocytes via the MAPK and PI3K/Akt signaling pathways.

A Schizophrenia-Related Genetic-Brain-Cognition Pathway Revealed in a Large Chinese Population.

BACKGROUND: In the past decades, substantial effort has been made to explore the genetic influence on brain structural/functional abnormalities in schizophrenia, as well as cognitive impairments. In this work, we aimed to extend previous studies to explore the internal mediation pathway among genetic factor, brain features and cognitive scores in a large Chinese dataset. METHODS: Gray matter (GM) volume, fractional amplitude of low-frequency fluctuations (fALFF), and 4522 schizophrenia-susceptible single nucleotide polymorphisms (SNP) from 905 Chinese subjects were jointly analyzed, to investigate the multimodal association. Based on the identified imaging-genetic pattern, correlations with cognition and mediation analysis were then conducted to reveal the potential mediation pathways. FINDINGS: One linked imaging-genetic pattern was identified to be group discriminative, which was also associated with working memory performance. Particularly, GM reduction in thalamus, putamen and bilateral temporal gyrus in schizophrenia was associated with fALFF decrease in medial prefrontal cortex, both were also associated with genetic factors enriched in neuron development, synapse organization and axon pathways, highlighting genes including CSMD1, CNTNAP2, DCC, GABBR2 etc. This linked pattern was also replicated in an independent cohort (166 subjects), which although showed certain age and clinical differences with the discovery cohort. A further mediation analysis suggested that GM alterations significantly mediated the association from SNP to fALFF, while fALFF mediated the association from SNP and GM to working memory performance. INTERPRETATION: This study has not only verified the impaired imaging-genetic association in schizophrenia, but also initially revealed a potential genetic-brain-cognition mediation pathway, indicating that polygenic risk factors could exert impact on phenotypic measures from brain structure to function, thus could further affect cognition in schizophrenia.

Successive grafting of poly(hydroxyethyl methacrylate) brushes and melamine onto chitosan microspheres for effective Cu(II) uptake.

Cross-linked chitosan (CCS) microspheres tethered with melamine-conjugated poly(hydroxyethyl methacrylate) (PHEMA) brushes were synthesized by combination of surface-initiated atom transfer radical polymerization (ATRP) of HEMA and subsequent covalent immobilization of melamine onto the chain ends of PHEMA brushes. The as-synthesized CCS microsphere was used as a novel adsorbent for effective uptake of Cu(II) ions from aqueous solution. Success in each functionalization step was ascertained by SEM, ATR-FTIR and XPS characterization. Batch adsorption experimental results demonstrated that the adsorption equilibrium of Cu(II) ions on the melamine-grafted CCS microsphere was rapidly established within 20 min, and the adsorption process was found to be governed by intra-particle diffusion and chemisorption processes. The Langmuir-fitted maximum adsorption capacity of Cu(II) ions on the as-synthesized CCS microspheres was as high as circa 4.67 mmol L-1 (299 mg g-1). The calculated thermodynamic parameters revealed an endothermic and spontaneous adsorption process of Cu(II) ions on the melamine-grafted CCS microspheres. XPS spectra revealed that the adsorption mechanism was attributed to coordination (or chelation) interactions between amino (or hydroxyl) groups with cationic Cu(II) ions.

Neural Cognition and Affective Computing on Cyber Language.

Characterized by its customary symbol system and simple and vivid expression patterns, cyber language acts as not only a tool for convenient communication but also a carrier of abundant emotions and causes high attention in public opinion analysis, internet marketing, service feedback monitoring, and social emergency management. Based on our multidisciplinary research, this paper presents a classification of the emotional symbols in cyber language, analyzes the cognitive characteristics of different symbols, and puts forward a mechanism model to show the dominant neural activities in that process. Through the comparative study of Chinese, English, and Spanish, which are used by the largest population in the world, this paper discusses the expressive patterns of emotions in international cyber languages and proposes an intelligent method for affective computing on cyber language in a unified PAD (Pleasure-Arousal-Dominance) emotional space.

Chitosan microsphere scaffold tethered with RGD-conjugated poly(methacrylic acid) brushes as effective carriers for the endothelial cells.

Endothelial cell-matrix interactions play a vital role in promoting vascularization of engineered tissues. The current study reports a facile and controllable method to develop a RGD peptide-functionalized chitosan microsphere scaffolds for rapid cell expansion of human umbilical vein endothelial cells (HUVECs). Functional poly(methacrylic acid) (PMAA) brushes are grafted from the chitosan microsphere surfaces via surface-initiated ATRP. Subsequent conjugation of RGD peptides on the pendent carboxyl groups of PMAA side chain is accomplished by carbodiimide chemistry to facilitate biocompatibility of the 3D CS scaffolding system. In vitro cell-loading assay of HUVECs exhibits a significant improvment of cell adhesion, spreading, and proliferation on the RGD peptide-immobilized CS microsphere surfaces.