A community challenge to predict clinical outcomes after immune checkpoint blockade in non-small cell lung cancer.

BACKGROUND: Predictive biomarkers of immune checkpoint inhibitor (ICI) efficacy are currently lacking for non-small cell lung cancer (NSCLC). Here, we describe the results from the Anti-PD-1 Response Prediction DREAM Challenge, a crowdsourced initiative that enabled the assessment of predictive models by using data from two randomized controlled clinical trials (RCTs) of ICIs in first-line metastatic NSCLC. METHODS: Participants developed and trained models using public resources. These were evaluated with data from the CheckMate 026 trial (NCT02041533), according to the model-to-data paradigm to maintain patient confidentiality. The generalizability of the models with the best predictive performance was assessed using data from the CheckMate 227 trial (NCT02477826). Both trials were phase III RCTs with a chemotherapy control arm, which supported the differentiation between predictive and prognostic models. Isolated model containers were evaluated using a bespoke strategy that considered the challenges of handling transcriptome data from clinical trials. RESULTS: A total of 59 teams participated, with 417 models submitted. Multiple predictive models, as opposed to a prognostic model, were generated for predicting overall survival, progression-free survival, and progressive disease status with ICIs. Variables within the models submitted by participants included tumor mutational burden (TMB), programmed death ligand 1 (PD-L1) expression, and gene-expression-based signatures. The best-performing models showed improved predictive power over reference variables, including TMB or PD-L1. CONCLUSIONS: This DREAM Challenge is the first successful attempt to use protected phase III clinical data for a crowdsourced effort towards generating predictive models for ICI clinical outcomes and could serve as a blueprint for similar efforts in other tumor types and disease states, setting a benchmark for future studies aiming to identify biomarkers predictive of ICI efficacy. TRIAL REGISTRATION: CheckMate 026; NCT02041533, registered January 22, 2014. CheckMate 227; NCT02477826, registered June 23, 2015.

Noval advance of histone modification in inflammatory skin diseases and related treatment methods.

Inflammatory skin diseases are a group of diseases caused by the disruption of skin tissue due to immune system disorders. Histone modification plays a pivotal role in the pathogenesis and treatment of chronic inflammatory skin diseases, encompassing a wide range of conditions, including psoriasis, atopic dermatitis, lupus, systemic sclerosis, contact dermatitis, lichen planus, and alopecia areata. Analyzing histone modification as a significant epigenetic regulatory approach holds great promise for advancing our understanding and managing these complex disorders. Additionally, therapeutic interventions targeting histone modifications have emerged as promising strategies for effectively managing inflammatory skin disorders. This comprehensive review provides an overview of the diverse types of histone modification. We discuss the intricate association between histone modification and prevalent chronic inflammatory skin diseases. We also review current and potential therapeutic approaches that revolve around modulating histone modifications. Finally, we investigated the prospects of research on histone modifications in the context of chronic inflammatory skin diseases, paving the way for innovative therapeutic interventions and improved patient outcomes.

Macrophage Membrane-Derived Biomimetic Nanoparticles for Treatment of Cytokine Release Syndrome.

Cytokine release syndrome (CRS) is a severe complication of infectious diseases like Coronavirus disease 2019 (COVID-19) that cause serious damage to public health. Currently, supportive therapy is still the main therapeutic strategy exists for CRS treatment. Here, we show the potential of macrophage membrane-derived biomimetic nanoparticles for CRS treatment. By fusing macrophage membrane on the surface of the PLGA nano core, we constructed biomimetic nanoparticles that inherited the membrane receptors from the "parental" macrophages, enabling the neutralization of CRS-related cytokines. We compared three types of macrophage membranes to screen out more effective biomimetic nanoparticles for CRS treatment. Our results show that M0 macrophage membrane-derived biomimetic nanoparticles could neutralize pro-inflammatory cytokines involved in CRS to the greatest extent and reduce organ damage in a mouse model.

Symbiotic microorganisms: prospects for treating atopic dermatitis.

INTRODUCTION: Atopic dermatitis (AD) is a common chronic recurrent inflammatory skin disease. The pathogenesis is unclear but may be related to genetic, immune, and environmental factors and abnormal skin barrier function. Symbiotic microorganisms in the gut and on the skin are associated with AD occurrence. AREAS COVERED: We discuss the metabolism and distribution of intestinal and skin flora and review their relationship with AD, summarizing the recent applications of intestinal and skin flora in AD treatment, and discussing the prospect of research on these two human microbiota systems and their influence on AD treatment. The PubMed database was searched to identify relevant publications from 1949 to 2020 for the bibliometric analysis of atopic dermatitis and symbiotic microorganisms. EXPERT OPINION: Many studies have suggested a potential contribution of microbes in the intestine and on the skin to AD. Bacteria living on the skin can aggravate AD by secreting numerous virulence factors. Moreover, the metabolism of intestinal flora can influence AD occurrence and development via the circulatory system. Current evidence suggests that by regulating intestinal and skin flora, AD can be treated and prevented.

Nano-engineered immune cells as "guided missiles" for cancer therapy.

Immune cells can actively regulate tumors or inflammatory sites and have good biocompatibility and safety. Currently, they are one of the most promising candidates for drug delivery systems. Moreover, immune cells can significantly extend the circulation time of nanoparticles and have broad-spectrum tumor-targeting properties. This article first introduces the immune cell types most commonly used in recent years, analyzes their advantages and disadvantages, and elucidates their application in anti-tumor therapy. Next, the various ways of loading nanoparticles on immune cells that have been used in recent years are summarized and simply divided into two categories: backpacks and Trojan horses. Finally, the two "mountains" that stand in front of us when using immune cells as cell carriers, off-target problems and effective release strategies, are discussed.

Design, Preparation, and Bioactivity Study of New Fusion Protein HB-NC4 in the Treatment of Osteoarthritis.

Osteoarthritis (OA) is now becoming the main disease that affects public health. There is no specific medicine used for OA in clinical application until now. Recently, several studies demonstrated that OA is closely related to the complement system, and some complement regulators such as N-terminal non-collagenous domain 4 (NC4) aimed at alleviating OA have shown a promising therapeutic effect. However, targeting ability is the main limitation for NC4. In this study, a fusion protein named heparin-binding domain-N-terminal non-collagenous domain 4 (HB-NC4) was proposed to solve this problem, which could provide a better way for OA treatment. First, HB-NC4 plasmid was constructed using ClonExpress II one-step ligation kit method. And Escherichia coli BL21 was utilized to express the fusion protein, Ni2+-sepharose, and a desalting gravity column were introduced to purify HB-NC4. The results showed that 0.84 mg HB-NC4 could be obtained from a 1 L culture medium with a purity higher than 92.6%. Then, the hemolytic assay was introduced to validate the anti-complement activity of HB-NC4; these results demonstrated that both HB-NC4 and NC4 had a similar anti-complement activity, which indicated that heparin-binding (HB) did not affect the NC4 structure. Targeting ability was investigated in vivo. HB-NC4 showed a higher affinity to cartilage tissue than NC4, which could prolong the retention time in cartilage. Finally, the destabilization of the medial meniscus (DMM) model was applied to investigate HB-NC4 pharmacodynamics in vivo. The results indicated that HB-NC4 significantly slowed cartilage degradation during the OA process. In summary, compared with NC4, HB-NC4 had better-targeting ability which could improve its therapeutic effect and prolonged its action time. It could be used as a new complement regulator for the treatment of OA in the future.

Aptamer-Functionalized Dendrimer Delivery of Plasmid-Encoding lncRNA MEG3 Enhances Gene Therapy in Castration-Resistant Prostate Cancer.

PURPOSE: The clinical management of patients with castration-resistant prostate cancer (CRPC) is difficult. However, novel treatment methods are gradually being introduced. Considering the adverse effects of traditional treatments, recent studies have investigated gene therapy as a method to combat CRPC; but, the application of long non-coding (lnc) RNA in gene therapy remains scarce, despite their promise. Therefore, it is imperative to develop a system that can efficiently deliver lncRNA for the treatment of CRPC. Here, we investigated the efficacy of a delivery system by introducing the plasmid-encoding tumor suppressor lncRNA MEG3 (pMEG3) in CRPC cells. MATERIALS AND METHODS: An EpDT3 aptamer-linked poly(amidoamine) (PAMAM) dendrimer targeting EpCAM was used to deliver pMEG3 in CRPC cells. The PAMAM-PEG-EpDT3/pMEG3 nanoparticles (NPs) were tested using in vitro cellular assays including cellular uptake, entry, and CCK-8 measurement, and tumor growth inhibition, histological assessment, and safety evaluations in in vivo animal models. RESULTS: The EpDT3 aptamer promoted endocytosis of PAMAM and PAMAM-PEG-EpDT3/pMEG3 NPs in CRPC cells. PAMAM-PEG-EpDT3/pMEG3 NPs exhibited a significant anti-CRPC effect, both in vivo and in vitro, when compared to that of unfunctionalized PAMAM-PEG/pMEG3 NPs. CONCLUSION: PAMAM-PEG-EpDT3/pMEG3 NPs can potentially improve gene therapy in CRPC cells.

Aqueous Two-Phase Emulsion Bioink-Enabled 3D Bioprinting of Porous Hydrogels.

3D bioprinting technology provides programmable and customizable platforms to engineer cell-laden constructs mimicking human tissues for a wide range of biomedical applications. However, the encapsulated cells are often restricted in spreading and proliferation by dense biomaterial networks from gelation of bioinks. Herein, a cell-benign approach is reported to directly bioprint porous-structured hydrogel constructs by using an aqueous two-phase emulsion bioink. The bioink, which contains two immiscible aqueous phases of cell/gelatin methacryloyl (GelMA) mixture and poly(ethylene oxide) (PEO), is photocrosslinked to fabricate predesigned cell-laden hydrogel constructs by extrusion bioprinting or digital micromirror device-based stereolithographic bioprinting. The porous structure of the 3D-bioprinted hydrogel construct is formed by subsequently removing the PEO phase from the photocrosslinked GelMA hydrogel. Three different cell types (human hepatocellular carcinoma cells, human umbilical vein endothelial cells, and NIH/3T3 mouse embryonic fibroblasts) within the 3D-bioprinted porous hydrogel patterns show enhanced cell viability, spreading, and proliferation compared to the standard (i.e., nonporous) hydrogel constructs. The 3D bioprinting strategy is believed to provide a robust and versatile platform to engineer porous-structured tissue constructs and their models for a variety of applications in tissue engineering, regenerative medicine, drug development, and personalized therapeutics.