Single-cell RNA sequencing highlights the role of proinflammatory fibroblasts, vascular endothelial cells, and immune cells in the keloid immune microenvironment.

BACKGROUND: Keloids, characterized by an aberrant wound-healing process and a highly complex immune microenvironment, pose significant challenges for clinical management. Fibroblasts and vascular endothelial cells (VEC) were identified as the leading cells of keloid development. However, their roles in the keloid immune landscape have yet to be thoroughly elucidated. METHODS: To explore the functional state of cells in the immune landscape of keloids, we conducted a single-cell RNA sequencing analysis on the tissue from three keloid lesions and two specimens of healthy skin. We simultaneously utilized available keloid data from the public database for external validation. RESULTS: Specific subsets, such as proinflammatory fibroblasts (piF) and VEC, were markedly elevated in lesional skin compared to normal skin. Subsequent differential gene expression and Gene Ontology analyses indicated that these subsets may be involved in shaping the microenvironment. In keloids, there is an increased expression of immune-associated genes (P < 0.05), including TNFRSF6B, HGF, and TGFB3, alongside a decreased expression of inflammatory chemokines in the piF. Moreover, the significant upregulation of immune suppressive genes (P < 0.05), including CD39, CD73, and HIF1A, suggested the potential involvement of VEC as a conditional immune subpopulation in the keloid microenvironment. Immune cell communication analysis revealed preferential enrichment of macrophages and Tregs, highlighting intensified macrophage-centered interactions within the keloid microenvironment. CONCLUSION: Our study highlighted the role of piF and VEC in the immune microenvironment of keloids for the first time, providing potential targets for therapeutic development.

Cellular liquid-liquid phase separation: Concept, functions, regulations, and detections.

Liquid-liquid phase separation is a multicomponent system separated into phases with different compositions and structures. It has been identified and explored in organisms after being introduced from the thermodynamic field. Condensate, the product of phase separation, exists in different scales of cellular structures, such as nucleolus, stress granules, and other organelles in nuclei or cytoplasm. And also play critical roles in different cellular behaviors. Here, we review the concept, thermodynamical and biochemical principles of phase separation. We summarized the main functions including the adjustment of biochemical reaction rates, the regulation of macromolecule folding state, subcellular structural support, the mediation of subcellular location, and intimately linked to different kinds of diseases, such as cancer and neurodegeneration. Advanced detection methods to investigate phase separation are collected and analyzed. We conclude with the discussion of anxiety of phase separation, and thought about how progress can be made to develop precise detection methods and disclose the potential application of condensates.

Two-year impact of COVID-19 pandemic on hospitalized patients with skin diseases in China.

To investigate the clinical characteristics of skin disorders among hospitalized patients before and during the coronavirus disease 2019 (COVID-19) pandemic, a retrospective study was conducted based on hospitalized patients with skin diseases from Xiangya Hospital of Central South University, the largest hospital in the south-central region of China, between January 1, 2018, and December 31, 2021. A total of 3039 hospitalized patients were enrolled in the study, including 1681 patients in the prepandemic group and 1358 patients in the pandemic group. The total number of hospitalized patients in the pandemic group decreased by 19.2%, with an increased proportion of patients over 60 years of age (39.8% vs. 35.8%). Moreover, compared with the prepandemic group, there were decreases in the occurrence of most skin diseases in the pandemic group, but the proportions of keratinolytic carcinoma (6.6% vs. 5.2%), dermatitis (24.0% vs. 18.9%), and psoriasis (18.0% vs. 14.8%) were higher in the pandemic group. In addition, longer hospital stays (ß = 0.07, SE = 0.02, P = 1.35 × 10-3 ) and higher hospital costs (ß = 0.06, SE = 0.03, p = 0.031) were found in the pandemic group through general linear models, even after the corresponding adjustment. In summary, the COVID-19 pandemic has had a lasting impact on patients with skin diseases, with fewer hospitalized patients, increased proportions of older patients, longer hospital stays, and increased hospital costs. These findings will facilitate better preparation for the most effective response to future pandemics.

CECR2 drives breast cancer metastasis by promoting NF-κB signaling and macrophage-mediated immune suppression.

Metastasis is the major cause of cancer-related deaths due to the lack of effective therapies. Emerging evidence suggests that certain epigenetic and transcriptional regulators drive cancer metastasis and could be targeted for metastasis treatment. To identify epigenetic regulators of breast cancer metastasis, we profiled the transcriptomes of matched pairs of primary breast tumors and metastases from human patients. We found that distant metastases are more immune inert with increased M2 macrophages compared to their matched primary tumors. The acetyl-lysine reader, cat eye syndrome chromosome region candidate 2 (CECR2), was the top up-regulated epigenetic regulator in metastases associated with an increased abundance of M2 macrophages and worse metastasis-free survival. CECR2 was required for breast cancer metastasis in multiple mouse models, with more profound effect in the immunocompetent setting. Mechanistically, the nuclear factor κB (NF-κB) family member v-rel avian reticuloendotheliosis viral oncogene homolog A (RELA) recruits CECR2 to increase chromatin accessibility and activate the expression of their target genes. These target genes include multiple metastasis-promoting genes, such as TNC, MMP2, and VEGFA, and cytokine genes CSF1 and CXCL1, which are critical for immunosuppression at metastatic sites. Consistent with these results, pharmacological inhibition of CECR2 bromodomain impeded NF-κB-mediated immune suppression by macrophages and inhibited breast cancer metastasis. These results reveal that targeting CECR2 may be a strategy to treat metastatic breast cancer.

Combination of radiotherapy and targeted therapy for melanoma brain metastases: a systematic review.

Radiotherapy is a mainstay of efficient treatment of brain metastases from solid tumors. Immunotherapy has improved the survival of metastatic cancer patients across many tumor types. However, targeted therapy is a feasible alternative for patients unable to continue immunotherapy or with poor outcomes of immunotherapy. The combination of radiotherapy and targeted therapy for the treatment of brain metastases has a strong theoretical underpinning, but data on the efficacy and safety of this combination is still limited. A systematic search of PubMed, Embase, Web of Science and the Cochrane library database was conducted. Eleven studies were included for a total of 316 patients. Median OS was about 6.2-17.8 months from radiotherapy. Weighted survival and local control at 1 and 2 years were correlated (50.1 and 17.8%, 90.7 and 14.7% at 1 and 2 year, respectively). Radiotherapy given before or concurrently to targeted therapy provided the best effect on the outcome. For patients with brain metastases from cutaneous melanoma, the addition of concurrent targeted therapy to brain radiotherapy can increase survival and provide long-term control.