Eulgi Lee

The identification of predictive biomarkers or models is necessary for the selection of patients who might benefit the most from immunotherapy. Seven histological features (signet ring cell [SRC], fibrous stroma, myxoid stroma, tumor-infiltrating lymphocytes [TILs], necrosis, tertiary lymphoid follicles, and ulceration) detected in surgically resected tissues (N = 44) were used to train a model. The presence of SRC became an optimal decision parameter for pathology alone (AUC = 0.78). Analysis of differentially expressed genes (DEGs) for the prediction of genomic markers showed that C-X-C motif chemokine ligand 11 (CXCL11) was high in responders (P < 0.001). Immunohistochemistry (IHC) was performed to verify its potential as a biomarker. IHC revealed that the expression of CXCL11 was associated with responsiveness (P = 0.003). The response prediction model was trained by integrating the results of the analysis of pathological factors and RNA sequencing (RNA-seq). When trained with the C5.0 decision tree model, the categorical level of the expression of CXCL11, a single variable, was shown to be the best model (AUC = 0.812). The AUC of the model trained with the random forest was 0.944. Survival analysis revealed that the C5.0-trained model (log-rank P = 0.01 for progression-free survival [PFS]; log-rank P = 0.012 for overall survival [OS]) and the random forest-trained model (log-rank P < 0.001 for PFS; log-rank P = 0.001 for OS) predicted prognosis more accurately than the PD-L1 test (log-rank P = 0.031 for PFS; log-rank P = 0.107 for OS).

Disruption of the skin microbial balance can exacerbate certain skin diseases and affect prognosis and treatment. Changes in the distribution and prevalence of certain microbial species on the skin, such as Staphylococcus aureus (SA), can impact the development of severe atopic dermatitis (AD) or psoriasis (Pso). A dysfunctional skin barrier develops in AD and Pso due to SA colonization, resulting in keratinization and chronic or progressive chronic inflammation. Disruption of the skin barrier following SA colonization can elevate the production of T helper 2 (Th2)-derived cytokines, which can cause an imbalance in Th1, Th2, and Th17 cells. This study examined the ability of potential therapeutic skin microbiomes, such as Cutibacterium avidum R-CH3 and Staphylococcus hominis R9, to inhibit SA biofilm formation and restore skin barrier function-related genes through the activation of the aryl hydrocarbon receptor (AhR) and the nuclear factor erythroid-2-related factor 2 (Nrf2) downstream target. We observed that IL-4/IL-13-induced downregulation of FLG, LOR, and IVL induced by SA colonization could be reversed by dual AhR/Nrf2 activation. Further, OVOL1 expression may be modulated by functional microbiomes via dual AhR/Nrf2 activation. Our results suggest that our potential therapeutic skin microbiomes can prevent SA-derived Th2-biased skin barrier disruption via IL-13 and IL-4-dependent FLG deregulation, STAT3 activation, and AhR-mediated STAT6 expression.

Recently, several capsular stroke models have been reported with different targets of destruction. This study was performed to establish an accurate internal capsule (IC) target for capsular stroke modeling in rats. We injected adeno-associated virus serotype 5 (AAV)-CaMKII-EYFP into forelimb motor cortex and AAV-CaMKII-mCherry into hindlimb motor cortex (n = 9) to anterogradely trace the pyramidal fibers and map their somatotopic distribution in the IC. On the basis of the neural tracing results, we created photothrombotic infarct lesions in rat forelimb and hindlimb motor fiber (FMF and HMF) areas of the IC (n = 29) and assessed motor behavior using a forelimb-use asymmetry test, a foot-fault test, and a single-pellet reaching test. We found that the FMFs and HMFs were primarily distributed in the inferior portion of the posterior limb of the IC, with the FMFs located largely ventral to the HMFs but with an area of partial overlap. Photothrombotic lesions in the FMF area resulted in persistent motor deficits. In contrast, lesions in the HMF area did not result in persistent motor deficits. These results indicate that identification of the somatotopic distribution of pyramidal fibers is critical for accurate targeting in animal capsular stroke models: only infarcts in the FMF area resulted in long-lasting motor deficits.

Abstract The skin supports a diverse microbiome whose imbalance is related to skin inflammation and diseases. Exposure to fine particulate matter (PM 2.5 ), a major air pollutant, can adversely affect the skin microbiota equilibrium. In this study, the effect and mechanism of PM 2.5 exposure in HaCaT keratinocytes were investigated. PM 2.5 stimulated the aryl hydrocarbon receptor (AhR) to produce reactive oxygen species (ROS) in HaCaT cells, leading to mitochondrial dysfunction and intrinsic mitochondrial apoptosis. We observed that the culture medium derived from a particular skin microbe, Staphylococcus epidermidis WF2R11, remarkably reduced oxidative stress in HaCaT cells caused by PM 2.5 -mediated activation of the AhR pathway. Staphylococcus epidermidis WF2R11 also exhibited inhibition of ROS-induced inflammatory cytokine secretion. Herein, we demonstrated that S. epidermidis WF2R11 could act as a suppressor of AhRs, affect cell proliferation, and inhibit apoptosis. Our results highlight the importance of the clinical application of skin microbiome interventions in the treatment of inflammatory skin diseases.