Harbin Medical University

Currently, surgical intervention remains the foundation in curing most solid tumors. Over the past few decades, even with rapid intraoperative tissue pathology assessment, the overall rate of positive surgical margins for tumors stagnated between 15 % and 60 %. The increased local recurrence rates and poor prognoses associated with various cancers, such as head and neck, brain, breast, lung, prostate, and gastrointestinal cancers, are linked to positive margins. Recently, driven by the concept of precise surgery, significant advancements have been reported in the intraoperative use of fluorescent contrast agents in the field of surgery. Molecular imaging via intraoperative fluorescence plays a guiding role in surgery, providing surgeons with visible fluorescent images. In clinical applications, fluorescent contrast agents can clearly delineate tumor boundaries, offering high recognition capacities and real-time guidance during surgery. Additionally, they can localize lymph node metastases, detect small metastatic lesions, and identify critical anatomical structures during surgery, thus reducing the risk of collateral damage. An ideal surgical guidance technology should lack radiation and display a high sensitivity and good resolution and an adjustable field of view, with rapid imaging. Enhancing the tissue penetration of fluorescence and targeting capacities of molecular probes are critical in providing more comprehensive tumor-related data. Additionally, screening and identifying other tumor biomarkers and more of their corresponding targeted molecular data are essential in enhancing the specificity of molecular imaging. Finally, the investigation and use of a wider range of near-infrared fluorescent dyes with improved biocompatibilities and imaging are critical in designing synthetic probes for application in intraoperative navigation. The development of novel, efficient, safe fluorescent contrast agents is a critical direction in current pharmaceutical research and development.

Psoriasis is a systemic inflammatory disorder that has a significant impact on the quality of life of patients. E74-like factor 3 (ELF3) is a common transcriptional mediator of inflammation, but the effect of ELF3 on psoriasis development and severity is poorly understood. In this study, we first collected clinical normal skin tissues and skin tissues of psoriasis patients to detect the mRNA and protein levels of ELF3 and found that ELF3 was highly expressed in psoriasis skin tissues. We further used the imiquimod (IMQ)-induced mice model to mimic the phenotypic changes of human psoriasis in vivo, which are manifested as scaling, epidermal hyperplasia, and erythema formation, but knockdown of ELF3 resulted in suppression of these phenomena. In addition, downregulation of ELF3 expression inhibited neoangiogenesis and inflammatory cell infiltration. On this basis, we further found that ELF3 promotes the proliferation, angiogenesis, and inflammatory response of human keratinocyte HaCaT in vitro. Mechanistically, we found that ELF3 transcriptionally activated the activity of the downstream factor ADAM metallopeptidase domain 8 (ADAM8) by dual luciferase assays, thereby exacerbating the severity of psoriasis. We concluded that ELF3 is a key target for exacerbating psoriasis pathologic manifestations and promoting disease progression.

Donor heart-resident C-C chemokine receptor 2 (CCR2⁺) macrophages induce the recruitment of CCR2⁺ monocytes to a transplanted hearts through the secretion of monocyte chemoattractant protein-1 (MCP-1), which mediates the incidence of acute rejection (AR). In this study, we synthesized MCP-1 peptide-modified polyethylene glycol-poly (lactic-co-glycolic) acid (PEG-PLGA) nanoparticles loaded with the sonosensitizer dihydroporphyrin e6 (Ce6) and administered them via intramyocardial injection and used in combination with sonodynamic therapy (SDT) to selectively deplete donor cardiac-resident and infiltrating CCR2⁺ macrophages. In vitro experiments confirmed that Ce6-NP-MCP-1 targets and has chemotactic effects on CCR2⁺ macrophages, thereby enhancing the therapeutic efficacy of STD. In mouse heart grafts, the chemotactic effect of Ce6-NP-MCP-1 on CCR2⁺ macrophages has been used to induce donor heart-resident and infiltrating CCR2⁺ macrophages to aggregate and phagocytose nanoparticles in combination with SDT to induce macrophage apoptosis. This therapy inhibits the number of donor heart-resident CCR2⁺ macrophages and downregulates the expression of proinflammatory cytokines and inflammatory infiltration. In addition, it significantly prolongs the allograft survival time. Therefore, CCR2-targeted nanoparticles combined with SDT for the selective depletion of donor heart-resident CCR2⁺ macrophages provide a promising paradigm for AR target treatment.