OBJECTIVE To explore the clinical features， diagnosis， treatment and management measures of multiple immune- related adverse event （irAE） after toripalimab treatment， in order to provide reference for the clinical management of similar cases. METHODS A retrospective analysis was conducted on a post-operative bladder cancer patient who developed various irAEs after toripalimab treatment. The patient’s medical history， laboratory tests， imaging studies， treatment course and outcomes were detailed. The Naranjo scale was used to assess the relationship between the irAEs and toripalimab. RESULTS The patient developed irAEs after receiving toripalimab， such as immune-related myocarditis， liver dysfunction， and myasthenia. According to the Naranjo scale evaluation， it was assessed that these adverse events were related to the administration of toripalimab. After high- dose corticosteroid pulse therapy and immunoglobulin immunomodulation， the patient’s symptoms were effectively relieved， with a improved trend in various physiological indicators and significant improvement in the degree of system/organ damage. CONCLUSIONS Toripalimab may lead to multiple irAEs， including immune-related myocarditis， liver injury， and myasthenia. Early recognition， timely diagnosis， and appropriate treatment of irAE are crucial for improving patient’s prognosis.

Recent data suggest that vascular endothelial growth factor receptor inhibitor (VEGFRi) can enhance the anti-tumor activity of the anti-programmed cell death-1 (anti-PD-1) antibody in colorectal cancer (CRC) with microsatellite stability (MSS). However, the comparison between this combination and standard third-line VEGFRi treatment is not performed, and reliable biomarkers are still lacking. We retrospectively enrolled MSS CRC patients receiving anti-PD-1 antibody plus VEGFRi (combination group, n=54) or VEGFRi alone (VEGFRi group, n=32), and their efficacy and safety were evaluated. We additionally examined the immune characteristics of the MSS CRC tumor microenvironment (TME) through single-cell and spatial transcriptomic data, and an MSS CRC immune cell-related signature (MCICRS) that can be used to predict the clinical outcomes of MSS CRC patients receiving immunotherapy was developed and validated in our in-house cohort. Compared with VEGFRi alone, the combination of anti-PD-1 antibody and VEGFRi exhibited a prolonged survival benefit (median progression-free survival: 4.4 vs. 2.0 months, P=0.0024; median overall survival: 10.2 vs. 5.2 months, P=0.0038) and a similar adverse event incidence. Through single-cell and spatial transcriptomic analysis, we determined ten MSS CRC-enriched immune cell types and their spatial distribution, including naive CD4⁺ T, regulatory CD4⁺ T, CD4⁺ Th17, exhausted CD8⁺ T, cytotoxic CD8⁺ T, proliferated CD8⁺ T, natural killer (NK) cells, plasma, and classical and intermediate monocytes. Based on a systemic meta-analysis and ten machine learning algorithms, we obtained MCICRS, an independent risk factor for the prognosis of MSS CRC patients. Further analyses demonstrated that the low-MCICRS group presented a higher immune cell infiltration and immune-related pathway activation, and hence a significant relation with the superior efficacy of pan-cancer immunotherapy. More importantly, the predictive value of MCICRS in MSS CRC patients receiving immunotherapy was also validated with an in-house cohort. Anti-PD-1 antibody combined with VEGFRi presented an improved clinical benefit in MSS CRC with manageable toxicity. MCICRS could serve as a robust and promising tool to predict clinical outcomes for individual MSS CRC patients receiving immunotherapy.
Humans ; Colorectal Neoplasms/drug therapy* ; Male ; Female ; Immunotherapy ; Middle Aged ; Aged ; Tumor Microenvironment/immunology* ; Retrospective Studies ; Microsatellite Instability ; Transcriptome ; Single-Cell Analysis ; Programmed Cell Death 1 Receptor/immunology* ; Gene Expression Profiling ; Immune Checkpoint Inhibitors/therapeutic use* ; Adult ; Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors*

Objective To investigate the effect of oxaliplatin on the activation of hepatic stellate cells(HSCs),as well as the association of oxaliplatin with microRNA-30a-5p and autophagy.Methods HSC-LX2 cells were cultured and divided into groups according to the following three protocols:control group,PDGF treatment group,oxaliplatin treatment group,oxaliplatin+PDGF treatment group;control group,microRNA-30a-5p transfection group,PDGF treatment group,microRNA-30a-5p transfection+PDGF treatment group;control group,3-MA group,microRNA-30a-5p inhibitor group,microRNA-30a-5p inhibitor+3-MA group.Western Blot was used to measure the expression of HSC activation-related proteins(Collagen-I and alpha-smooth muscle actin[α-SMA])and HSC autophagy-related proteins(Beclin-1,P62,and LC3B);LysoTracker staining and immunofluorescence assay were used to measure the expression of LC3B autophagosomes;RT-PCR was used to measure the expression level of microRNA-30a-5p;bioinformatics techniques were used to predict the potential targets of microRNA-30a-5p in HSCs.The independent-samples t test was used for comparison of normally distributed continuous data between two groups;a one-way analysis of variance was used for comparison between multiple groups,and the least significant difference t-test was used for further comparison between two groups.Results After the cells were treated with oxaliplatin,RT-PCR results showed that the oxaliplatin treatment group had a significantly higher expression level of microRNA-30a-5p than the control group(P＜0.01);Western Blot showed that the oxaliplatin treatment group had significant reductions in the expression levels of the HSC activation-related proteins α-SMA and Collagen-Ⅰ and the autophagy-related proteins Beclin 1 and LC3BⅡ/Ⅰ(all P＜0.001);immunofluorescence assay showed that the oxaliplatin treatment group had a significantly lower number of autophagosomes than the control group(P＜0.05).After HSC-LX2 cells were transfected with microRNA-30a-5p mimic,compared with the control group,the microRNA-30a-5p mimic group had significant reductions in the expression levels of the autophagy-related proteins Beclin 1 and LC3BⅡ/Ⅰ(P＜0.05)and the HSC activation-related protein Collagen-Ⅰ(P＜0.001);after HSC-LX2 cells were transfected with microRNA-30a-5p inhibitor,Western Blot showed that compared with the control group,the microRNA-30a-5p inhibitor group had significant increases in the expression levels of the HSC activation-related proteins Collagen-Ⅰ and α-SMA and the autophagy-related protein Beclin 1(t=2.41,2.32,and 4.57,all P＜0.05).Western Blot showed that compared with the control group,the microRNA-30a-5p inhibitor group had significant increases in the expression levels of the HSC autophagy-related protein Beclin 1 and the HSC activation-related protein α-SMA(both P＜0.05),and after the treatment with the autophagy inhibitor 3-MA,there were no significant differences in the expression of these proteins between the two groups(P＞0.05).The bioinformatics analysis using TargetScan,PicTar,and miRanda databases showed that the autophagy-related protein Beclin-1 might be a potential target of miRNA-30a-5p.Conclusion Oxaliplatin can inhibit the activation of HSCs by upregulating the expression of microRNA-30a-5p,which provides new ideas and a new target for the treatment of liver fibrosis.

Objective:To investigate molecular mechanisms underlying the inflammatory response induced by Cutibacterium acnes ( C. acnes) biofilms in human primary keratinocytes. Methods:A C. acnes biofilm model was established in vitro, and confocal fluorescence microscopy was performed to examine its three-dimensional structure. The cultured human primary keratinocytes were divided into 3 groups: a dimethyl sulfoxide (DMSO) control group (treated with 0.01% DMSO alone), a C. acnes suspension group (co-incubated with C. acnes suspensions), and a C. acnes biofilm group (co-incubated with C. acnes biofilms). Real-time fluorescence-based quantitative PCR (RT-qPCR) was performed to determine the relative mRNA expression of interleukin (IL) -6, IL-8, and tumor necrosis factor (TNF) -α in the groups after 6-hour culture, enzyme-linked immunosorbent assay to detect the free protein levels of IL-6, IL-8, and TNF-α in the groups after 24-hour culture, and Western blot analysis to determine the protein expression of Toll-like receptor 2 (TLR2) in keratinocytes. In addition, some human primary keratinocytes were pretreated with key molecular blockers targeting the TLR2/mitogen-activated protein kinase (MAPK) /nuclear factor (NF) -κB signaling pathway (C29, ST2825, BAY11-7082, SB203580, U0126-EtOH), and then co-incubated with C. acnes biofilms; the DMSO control group and the C. acnes biofilm group receiving no pretreatment were simultaneously set as negative and positive controls, respectively. The mRNA and free protein expression levels of IL-6, IL-8, and TNF-α were then detected in the above groups. One-way analysis of variance was used for comparisons among multiple groups, and the Bonferroni method was used for multiple comparisons. Results:Confocal fluorescence microscopy demonstrated a three-dimensional C. acnes biofilm structure resembling a lawn, and the biofilm grew well. RT-qPCR and ELISA showed significant differences in the mRNA and free protein expression levels of IL-6, IL-8, and TNF-α among the C. acnes biofilm group, C. acnes suspension group and DMSO control group (mRNA: F = 89.70, 312.17, 46.09, respectively, all P < 0.001; free protein: F = 886.12, 634.25, 307.01, respectively, all P < 0.001) ; in detail, the mRNA and free protein expression levels of IL-6, IL-8, and TNF-α were significantly higher in the C. acnes biofilm group than in the C. acnes suspension group and DMSO control group (all P < 0.001) ; the C. acnes suspension group showed significantly increased expression levels of IL-6 mRNA and TNF-α free protein compared with the DMSO control group ( P < 0.001, = 0.003, respectively), while there were no significant differences in the expression of IL-6 free protein, TNF-α mRNA, or IL-8 mRNA and free protein between the 2 groups (all P > 0.05). Western blot analysis showed that the TLR2 protein expression was significantly higher in the C. acnes suspension group and C. acnes biofilm group than in the DMSO control group. After the pretreatment with molecular blockers targeting the MAPK/NF-κB signaling pathway and co-incubation with C. acnes biofilms, the mRNA and free protein expression levels of IL-6, IL-8 and TNF-α were all significantly lower in the C29 group, ST2825 group, BAY11-7082 group, SB203580 group, U0126-EtOH group, as well as in the DMSO control group compared with the C. acnes biofilm group (all P < 0.05) . Conclusion:The C. acnes biofilms exhibited a strong ability to induce inflammatory responses in human keratinocytes, possibly through the activation of the TLR2/MAPK/NF-κB signaling pathway.

Acne vulgaris is a clinically common chronic inflammatory skin disease. Currently, severity grading and efficacy assessment in acne vulgaris mainly rely on dermatologists′ clinical experience. In recent years, skin imaging techniques have raised great attention in the diagnosis and treatment of various skin diseases, owing to their non-invasive, real-time, objective and reproducible properties. This review summarizes the progress in application of various skin imaging techniques, including dermoscopy, reflectance confocal microscopy, optical coherence tomography and high-frequency ultrasound imaging, in the research of acne vulgaris, aiming to provide new ideas for basic research of acne vulgaris, as well as its clinical diagnosis and assessment of therapeutic efficacy.

The Janus kinase (JAK) -signal transducer and activator of transcription (STAT) signaling pathway is closely related to the occurrence of psoriasis. Various cytokines, including interleukin (IL) -23, IL-22, interferon (IFN) -γ, etc., can promote some key pathologic processes (such as the proliferation and abnormal differentiation of keratinocytes, and infiltration of inflammatory cells) via the JAK-STAT pathway in psoriasis, which suggests that targeting JAK-STAT pathway is a new strategy for the treatment of psoriasis. In recent years, small-molecule JAK inhibitors have shown good efficacy and safety in the treatment of psoriasis, and drugs targeting STAT pathway have been under development, which provide more treatment options for psoriasis. This review summarizes progress in drugs targeting the JAK-STAT signaling pathway in the treatment of psoriasis.

Lung cancer remains the leading cause of cancer deaths worldwide and is the most common cancer in males. Immune-checkpoint inhibitors (ICIs) that target programmed cell death protein-1 (PD-1) or programmed cell death-ligand 1 (PD-L1) have achieved impressive efficacy in the treatment of non-small-cell lung cancer (NSCLC) (Pardoll, 2012; Champiat et al., 2016; Gao et al., 2022). Although ICIs are usually well tolerated, they are often accompanied by immune-related adverse events (irAEs) (Doroshow et al., 2019). Non-specific activation of the immune system produces off-target immune and inflammatory responses that can affect virtually any organ or system (O'Kane et al., 2017; Puzanov et al., 2017). Compared with adverse events caused by chemotherapy, irAEs are often characterized by delayed onset and prolonged duration and can occur in any organ at any stage of treatment, including after cessation of treatment (Puzanov et al., 2017; von Itzstein et al., 2020). They range from rash, pneumonitis, hypothyroidism, enterocolitis, and autoimmune hepatitis to cardiovascular, hematological, renal, neurological, and ophthalmic irAEs (Nishino et al., 2016; Kumar et al., 2017; Song et al., 2020). Hence, we conducted a retrospective study to identify validated factors that could predict the magnitude of the risk of irAEs in patients receiving PD-1/PD-L1 inhibitors; our approach was to analyze the correlation between the clinical characteristics of patients at the start of treatment and relevant indicators such as hematological indices and the risk of developing irAEs. Then, we developed an economical, practical, rapid, and simple model to assess the risk of irAEs in patients receiving ICI treatment, as early as possible.
Male ; Humans ; Carcinoma, Non-Small-Cell Lung/drug therapy* ; Lung Neoplasms/drug therapy* ; Immune Checkpoint Inhibitors/adverse effects* ; Programmed Cell Death 1 Receptor ; Retrospective Studies ; Apoptosis

Objective:To investigate the effect of upper limb pillow position on hemodynamic and safety of patients undergoing cerebellopontine angle tumor resection.Methods:Eighty-four patients receiving cerebellopontine angle tumor resection in our hospital from January 2016 to December 2019 were randomly divided into the experimental group (42 cases) and the control group (42 cases). Patients in the control group were placed in routine upper limb position, while patients in the experimental group were placed in upper limb pillow position. The data including systolic pressure, diastolic pressure, heart rate, saturation of blood oxygen were recorded on admission of operation room, completing placing body position, 30 minutes and 60 minutes after operation and after finishing the operation. The numbness/soreness of upper limbs and pressure injury rate was compared between the experimental group and the control group.Results:The rate of numbness/soreness of upper limbs were 2.4% (1/42) in the experimental group, 19.1%(8/42) in the control group, the differences were statistically significant ( χ2 value was 6.098, P<0.05). The stage 1 pressure injury were 2 cases in the experimental group, stage 1 and 2 pressure injury were 6 cases and 2 cases, respectively in the control group, the differences were statically significant ( Z value was 2.039, P<0.05). Conclusion:Upper limb pillow position of the operation side can reduce postoperative complication of patients undergoing cerebellopontine angle tumor resection, but will not increase the risk of abnormal hemodynamic fluctuation.

Objective:To observe the effect of feedback pulmonary rehabilitation guidance on self-management of elderly patients with stable chronic obstructive pulmonary disease (COPD).Methods:Ninety-four elderly patients with stable COPD that visited the outpatient department between January 2018 and January 2019 were selected. Block randomization methods were used to divide the patients into two groups: routine lung rehabilitation instruction group (referred to as the “routine group”) and feedback lung rehabilitation group (referred to as the “feedback group”). The feedback group received the instruction of feedback pulmonary rehabilitation guidance, while the routine group received the instruction of routine pulmonary rehabilitation guidance. The quality of life and the self-management ability of the two groups before and after the intervention were compared.Results:There was no statistically significant difference between the scores of the feedback and routine groups before the intervention of the COPD-specific self-management scale ( P>0.05). In the feedback group, the scores of emotional management, daily life management, symptom management, self-efficacy management, and information management on the COPD-specific self-management scale after the intervention were 45.01±5.31, 53.10±6.60, 25.88±3.03, 35.01±5.31, and 24.32±4.20, respectively, whereas those for the routine group were 40.23±5.19, 48.02±6.58, 22.88±3.01, 31.01±4.80, and 20.30±2.88, respectively. The scores of the feedback group were higher than the routine group and the difference was significant ( P<0.001). There was no significant difference between the feedback group and the routine group before the intervention of the respiratory disease questionnaire, i.e., the airways questionnaire 20-revised (AQ20-R) score ( P>0.05). The AQ20-R score of the feedback group after the intervention was 7.22±1.08, which was lower than that of the routine group (9.01±2.01); the difference was significant ( P<0.001). Conclusion:The application of feedback pulmonary rehabilitation guidance in the self-management of elderly patients with stable COPD can improve both their self-management ability and quality of life.

Objective? To define the difficulty coefficient of Operating Room nursing items which is suitable for difficulty evaluation and can represent the workload of Operating Room nursing. Methods? From January 2017 to March 2018, through literature review, questionnaire survey and expert demonstration meeting, the nursing work items and operational difficulty indicators suitable for difficulty evaluation in Operating Room were determined. The weight of difficulty indicators was determined by analytic hierarchy process. Fifteen experts were selected for three rounds of Delphi inquiry. The coefficients of difficulty were determined by weighted linear method. Results? Finally, the difficulty coefficients of 68 operating room nursing items were obtained. The top three difficulty coefficients were "position placement and observation of lateral traction bed (7.268 7)", "position placement and observation of fixed skull (7.254 0)" and "position and observation of skull-brain frame lateral decubitus position (7.243 3)"; the last three difficulty coefficients were "horizontal supine position placement and observation (2.178 2)" and "sterile sheet laying (2.046 0)" , "no-contact wearing of sterile gloves (1.000 0)". Conclusions? This study defines 68 difficulty coefficients of operating room nursing work items which are suitable for difficulty evaluation and can represent the workload of Operating Room nursing. It can quantify the difficulty of Operating Room nursing work items and enhance the rationality of Operating Room nursing workload counting.