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Occurrence and development of cancers are governed by complex networks of interacting intercellular and intracellular signals. The technology of single-cell RNA sequencing (scRNA-seq) provides an unprecedented opportunity for dissecting the interplay between the cancer cells and the associated microenvironment. Here we combined scRNA-seq data with clinical bulk gene expression data to develop a computational pipeline for identifying the prognostic and predictive signature that connects cancer cells and microenvironmental cells. The pipeline was applied to glioma scRNA-seq data and revealed a tumor-associated microglia/macrophage-mediated EGFR/ERBB2 feedback-crosstalk signaling module, which was defined as a multilayer network biomarker (MNB) to predict survival outcome and therapeutic response of glioma patients. We used publicly available clinical data sets from large cohorts of glioma patients to examine the prognostic significance and predictive accuracy of the MNB, which outperformed conventional gene biomarkers and other methods. Additionally, the MNB was found to be predictive of the sensitivity or resistance of glioma patients to molecularly targeted therapeutics. Moreover, the MNB was an independent and the strongest prognostic factor when adjusted for clinicopathologic risk factors and other existing gene signatures. The robustness of the MNB was further tested on additional data sets. Our study presents a promising scRNA-seq transcriptome-based multilayer network approach to elucidate the interactions between tumor cell and tumor-associated microenvironment and to identify prognostic and predictive signatures of cancer patients. The proposed MNB method may facilitate the design of more effective biomarkers for predicting prognosis and therapeutic resistance of cancer patients. [ABSTRACT FROM AUTHOR]

Objective Methods Results Conclusion To explore T cell‐intrinsic mechanisms underpinning the mal‐differentiation of tissue‐resident memory T (Trm) cells in patients with rheumatoid arthritis (RA).Circulating T cells from patient with RA and healthy individuals were used for Trm cell differentiation. The role of Hobit in Trm differentiation was investigated through targeted silencing experiments. Psmb5 expression regulation was explored by identifying BRD2 as a key transcription factor, with the interaction validated through chromatin immunoprecipitation‐quantitative polymerase chain reaction. The impact of BRD2 succinylation on Trm differentiation was examined by manipulating succinyl‐CoA levels in T cells. Humanized NSG chimeras representing synovitis provided insights into Trm infiltration in RA synovitis and were used for translational experiments.In patients with RA, a notable predisposition of CD4+ T cells toward differentiation into Trm cells was observed, demonstrating a positive correlation with the disease activity score 28. Remarkably, Hobit was a pivotal facilitator in the formation of RA CD4+ Trm cells. Mechanistic studies unveiled the dysregulation of proteasomal Psmb5 in T cells of patients with RA as the key factor contributing to elevated Hobit protein levels. The deficiency of proteasomal Psmb5 was intricately linked to BRD2, with succinylation exerting a significant impact on Psmb5 transcription and Trm cell differentiation. This heightened BRD2 succinylation was attributed to elevated levels of mitochondrial succinyl‐CoA in RA T cells. Consequently, targeting succinyl‐CoA within CD4+ T cells controlled the inflammation of synovial tissues in humanized chimeras.Mitochondrial succinyl‐CoA fosters the succinylation of BRD2, resulting in compromised transcription of proteasomal Psmb5 and the differentiation of Trm cells in RA. [ABSTRACT FROM AUTHOR]

Pain caused by lumbar disc herniation (LDH) severely compromises patients' quality of life. The combination of steroid and local anesthetics is routinely employed in clinics to alleviate LDH-induced pain. However, the approach only mediates transient efficacy and requires repeated and invasive lumbar epidural injections. Here a paravertebrally-injected multifunctional hydrogel that can efficiently co-load and controlled release glucocorticoid betamethasone and anesthetics ropivacaine for sustained anti-inflammation, reactive oxygen species (ROS)-removal and pain relief in LDH is presented. Betamethasone is conjugated to hyaluronic acid (HA) via ROS-responsive crosslinker to form amphiphilic polymer that self-assemble into particles with ropivacaine loaded into the core. Solution of drug-loaded particles and thermo-sensitive polymer rapidly forms therapeutic hydrogel in situ upon injection next to the herniated disc, thus avoiding invasive epidural injection. In a rat model of LDH, multifunctional hydrogel maintains the local drug concentration 72 times longer than free drugs and more effectively inhibits the expression of pro-inflammatory cytokines and pain-related molecules including cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE 2 ). Therapeutic hydrogel suppresses the LDH-induced pain in rats for 12 days while the equivalent dose of free drugs is only effective for 3 days. This platform is also applicable to ameliorate pain caused by other spine-related diseases., (© 2024 Wiley‐VCH GmbH.)