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Immune checkpoint inhibitors (ICI) represent new anticancer agents and have been used worldwide. However, ICI can potentially induce life-threatening severe cutaneous adverse reaction (SCAR), such as Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), hindering continuous ICI therapy. We examine 6 cohorts including 25 ICI-induced SJS/TEN patients and conduct single-cell RNA sequencing (scRNA-seq) analysis, which shows overexpression of macrophage-derived CXCL10 that recruits CXCR3 + cytotoxic T lymphocytes (CTL) in blister cells from ICI-SJS/TEN skin lesions. ScRNA expression profiles and ex vivo blocking studies further identify TNF signaling as a pathway responsible for macrophage-derived CXCL10 and CTL activation. Based on the trajectory analysis, ICI-activated T cells from whole blood are proposed to serve as the initial cells involved in inflammation, that lead to monocytes differentiating into macrophages and increasing their susceptibility to migrate to the lesion sites. Compared with systemic corticosteroids treatment, ICI-induced SJS/TEN patients treated with biologic TNF blockade showed a significantly rapid recovery and no recurrence of SCAR with continuous ICI therapy. Our findings identify that macrophage-eliciting CTL contribute to the pathogenesis of ICI-induced epidermal necrolysis and provide potential therapeutic targets for the management and prevention of SCAR induced by ICI therapy. As immune checkpoint therapy is more frequently used for cancer, side effects such as Stevens-Johson syndrome / toxic epidermal necrolysis (SJS/TEN) are becoming more common. Here the authors use single cell transcriptomics to implicate TNF and CXCL10 in recruitment of CXCR3 + cytotoxic T cell in SJS/TEN skin lesions.

Cytotoxic T lymphocyte-mediated (CTL-mediated) severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), are rare but life-threatening adverse reactions commonly induced by drugs. Although high levels of CTL-associated cytokines, chemokines, or cytotoxic proteins, including TNF-α and granulysin, were observed in SJS-TEN patients in recent studies, the optimal treatment for these diseases remains controversial. We aimed to evaluate the efficacy, safety, and therapeutic mechanism of a TNF-α antagonist in CTL-mediated SCARs. We enrolled 96 patients with SJS-TEN in a randomized trial to compare the effects of the TNF-α antagonist etanercept versus traditional corticosteroids. Etanercept improved clinical outcomes in patients with SJS-TEN. Etanercept decreased the SCORTEN-based predicted mortality rate (predicted and observed rates, 17.7% and 8.3%, respectively). Compared with corticosteroids, etanercept further reduced the skin-healing time in moderate-to-severe SJS-TEN patients (median time for skin healing was 14 and 19 days for etanercept and corticosteroids, respectively; P = 0.010), with a lower incidence of gastrointestinal hemorrhage in all SJS-TEN patients (2.6% for etanercept and 18.2% for corticosteroids; P = 0.03). In the therapeutic mechanism study, etanercept decreased the TNF-α and granulysin secretions in blister fluids and plasma (45.7%-62.5% decrease after treatment; all P < 0.05) and increased the Treg population (2-fold percentage increase after treatment; P = 0.002), which was related to mortality in severe SJS-TEN. The anti-TNF-α biologic agent etanercept serves as an effective alternative for the treatment of CTL-mediated SCARs. ClinicalTrials.gov NCT01276314. Ministry of Science and Technology of Taiwan.

BACKGROUND. Cytotoxic T lymphocyte-mediated (CTL-mediated) severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), are rare but life-threatening adverse reactions commonly induced by drugs. Although high levels of CTL-associated cytokines, chemokines, or cytotoxic proteins, including TNF-[alpha] and granulysin, were observed in SJS-TEN patients in recent studies, the optimal treatment for these diseases remains controversial. We aimed to evaluate the efficacy, safety, and therapeutic mechanism of a TNF-[alpha] antagonist in CTL-mediated SCARs. METHODS. We enrolled 96 patients with SJS-TEN in a randomized trial to compare the effects of the TNF-[alpha] antagonist etanercept versus traditional corticosteroids. RESULTS. Etanercept improved clinical outcomes in patients with SJS-TEN. Etanercept decreased the SCORTEN-based predicted mortality rate (predicted and observed rates, 17.7% and 8.3%, respectively). Compared with corticosteroids, etanercept further reduced the skin-healing time in moderate-to-severe SJS-TEN patients (median time for skin healing was 14 and 19 days for etanercept and corticosteroids, respectively; P = 0.010), with a lower incidence of gastrointestinal hemorrhage in all SJS-TEN patients (2.6% for etanercept and 18.2% for corticosteroids; P = 0.03). In the therapeutic mechanism study, etanercept decreased the TNF-[alpha] and granulysin secretions in blister fluids and plasma (45.7%-62.5% decrease after treatment; all P < 0.05) and increased the Treg population (2-fold percentage increase after treatment; P = 0.002), which was related to mortality in severe SJS-TEN. CONCLUSIONS. The anti-TNF-[alpha] biologic agent etanercept serves as an effective alternative for the treatment of CTL-mediated SCARs. TRIAL REGISTRATION. ClinicalTrials.gov NCT01276314. FUNDING. Ministry of Science and Technology of Taiwan.

Objective:To compare the adverse maternal and neonatal outcomes of multiple pregnancy and singleton pregnancy from multiple medical centers in Beijing.Methods:Data concerning maternal and neonatal adverse outcomes in multiple and singleton pregnancies were collected from 15 hospitals in Beijing by a systemic cluster sampling survey conducted from 20 June to 30 November 2013.The SPSS software (version 20.0) was used for data analysis.The x2 test was used tbr statistical analyses.Results:The rate of caesarean deliveries was much higher in women with multiple pregnancies (85.8％) than that in women with singleton pregnancies (42.6％,X2 =190.8,P ＜ 0.001).The incidences of anemia (X2 =40.023,P ＜ 0.001),preterm labor (X2 =1021.172,P ＜ 0.001),gestational diabetes mellitus (X2 =9.311,P ＜ 0.01),hypertensive disorders (X2 =122.708,P ＜ 0.001)and post-partum hemorrhage (X2-48.550,P ＜ 0.001) was significantly increased with multiple pregnancy.In addition,multiple pregnancy was associated with a significantly higher rate of small-for-gestational-age infants (X2 =92.602,P ＜ 0.001),low birth weight (X2 =1141.713,P ＜ 0.001),and neonatal intensive care unit (NICU) admission (X2 =340.129,P＜ 0.001).Conclusions:Multiple pregnancy is a significant risk factor for adverse maternal and neonatal outcomes in Beijing.Improving obstetric care for multiple pregnancy,particularly in reducing preterm labor,is required to reduce the risk to mothers and infants.

Aim： To assess the roles of extracellular signal-regulated kinase （ERK）, p38, and CDi51-integrin complexes on proliferation, migration, and tube formation activities of CD151-induced human umbilical vein endothelial cells （HUVECs）. Methods： CD151, anti-CD151 and CD151-AAA mutant were inserted into recombinant adeno-associated virus （rAAV） vectors and used to transfect HUVECs. After transfection, the expression of CD15i was measured. Proliferation was assessed using the 3-[4,5-dimethylthiazol- 2-yl]-2,5-diphenyl tetrazolium bromide （MTT） assay. Cell migration was evaluated in Boyden transwell chambers using FBS as the chemotactic stimulus. The tube formation assay was performed on matrigel. The potential involvement of various signaling pathways was explored using selective inhibitors. Results： CD151 gene delivery increased the expression of CD151 at both the mRNA and protein levels. Overexpression of CD151 promoted cell proliferation, migration and tube formation in vitro, and phosphorylation of ERK was also increased. Further, CD151- induced cell proliferation, migration, and tube formation were attenuated by the ERK inhibitor PD98059 （20 μmol/L） but not by a p38 inhibitor （SB203580, 20 μmol/L）. Moreover, there was no significant difference in CD151 protein expression between the CD151 group and the CD151-AAAgroup, but the CD151-AAA mutant abrogated cellular proliferation, migration, and tube formation and decreased the phosphorylation of ERK. Conclusion： This study suggests that activation of the ERK signaling pathway may be involved in the angiogenic effects of CD151. Activation of ERK was dependent on the formation of CD151-integrin complexes. Therefore modulation of CD151 may be as a novel therapeutic strategy for regulating angiogenesis.

Gamified learning (GL) plays a crucial role in enhancing both the efficiency and engagement of K-12 students' learning experiences. However, there are few studies to explore whether the GL specially designed for the curriculum will affect the cultivation of students' ability. An extensive search of publications from 2013 to 2023 was conducted across three databases: Web of Science, ERIC, and Scopus. Citations and extracted data from the articles were independently assessed. Experimental or quasi-experimental studies specifically investigating the impact of GL on K-12 students' learning outcomes were considered eligible according to the inclusion criteria. This study aims to explore which type of GL had a more significant impact on K-12 students' holistic abilities, including cognitive and non-cognitive abilities, when compared between specialized GL designed for the study's curriculum and directly using pre-existing GL models. Results revealed that GL had upper-medium effects on K-12 students' Learning outcomes (ES = 0.701, p ＜ .001), and specialized GL designed for the study's curriculum showed superior effectiveness and had a more significant positive influence (ES = 0.821, p ＜ .001). Furthermore, moderator analyses showed that experimental cycle, levels of schooling and disciplines moderated the effects of GL. In conclusion, we propose that GL in K-12 needs to be tailored to different levels of schooling and disciplines, with appropriate experimental cycle to promote and stimulate learning efficiency of K-12 education. However, future research should expand data sources, incorporate more diverse moderator variables, and include multilingual literature to enhance the comprehensiveness and generalizability of the findings.

Traditionally, airborne time-domain electromagnetic （ATEM） data are inverted to derive the earth model by iteration. However, the data are often highly correlated among channels and consequently cause ill-posed and over-determined problems in the inversion. The correlation complicates the mapping relation between the ATEM data and the earth parameters and thus increases the inversion complexity. To obviate this, we adopt principal component analysis to transform ATEM data into orthogonal principal components （PCs） to reduce the correlations and the data dimensionality and simultaneously suppress the unrelated noise. In this paper, we use an artificial neural network （ANN） to approach the PCs mapping relation with the earth model parameters, avoiding the calculation of Jacobian derivatives. The PC-based ANN algorithm is applied to synthetic data for layered models compared with data-based ANN for airborne time-domain electromagnetic inversion. The results demonstrate the PC-based ANN advantages of simpler network structure, less training steps, and better inversion results over data-based ANN, especially for contaminated data. Furthermore, the PC-based ANN algorithm effectiveness is examined by the inversion of the pseudo 2D model and comparison with data-based ANN and Zhody＇s methods. The results indicate that PC-based ANN inversion can achieve a better agreement with the true model and also proved that PC-based ANN is feasible to invert large ATEM datasets.

Dear Editor, Embryonic stem cells （ESCs） are pluripotent cells established from early stage embryos that maintain the ability to differentiate into three-germ layer cells. This unique characteristic is the basis for various applications of ESC technology. To successfully use ESCs in these applications, researchers have explored a variety of in vitro methods to maintain the self-perpetuating, naive, undifferentiated state during long-term culture of ESCs.

Aim： Monoterpene glycosides derived from Paeonia lactiflora roots （Chishao） are believed to be pharmacologically important for the antiseptic herbal injection XueBiJing. This study was designed to characterize the pharmacokinetics and disposition of monoterpene glycosides. Methods： Systemic exposure to Chishao monoterpene glycosides was assessed in human subjects receiving an intravenous infusion and multiple infusions of XueBiJing injection, followed by assessment of the pharmacokinetics of the major circulating compounds. Supportive rat studies were also performed. Membrane permeability and plasma-protein binding were assessed in vitro. Results： A total of 18 monoterpene glycosides were detected in XueBiJing injection （content levels, 0.001-2.47 mmol/L）, and paeoniflorin accounted for 85.5% of the total dose of monoterpene glycosides detected. In human subjects, unchanged paeoniflorin exhibited considerable levels of systemic exposure with elimination half-lives of 1.2-1.3 h; no significant metabolite was detected. Oxypaeoniflorin and albiflorin exhibited low exposure levels, and the remaining minor monoterpene glycosides were negligible or undetected. Glomerular-filtration-based renal excretion was the major elimination pathway of paeoniflorin, which was poorly bound to plasma protein. In rats, the systemic exposure level of paeoniflorJn increased proportionally as the dose was increased. Rat lung, heart and liver exposure levels of paeoniflorin were lower than the plasma level, with the exception of the kidney level, which was 4.3-fold greater than the plasma level; brain penetration was limited by the poor membrane permeability. Conclusion： Due to its significant systemic exposure and appropriate pharmacokinetic profile, as well as previously reported antiseptic properties, paeoniflorin is a promising XueBiJing constituent of therapeutic importance.

OCT4, a member of the POU family of gene products, is an octamer motif-binding transcription factor. As it is known to play a crucial role in cancer processes including proliferation, invasion, and chemoradioresistance, it is important to identify the direct targets of OCT4 in living cancer cells. Here, chromatin immunoprecipitation-sequencing （ChlP-seq） was used to identify OCT4 binding sites in glioblastoma cancer cells. The results showed that 5438 OCT4 binding sites were localized in the glioblastoma cancer genome and that these sites contained a consensus sequence TTTkswTw （k=T or G, s=C or G, w=A or T）, which occurred 3931 times in 2312 OCT4 binding regions. Furthermore, binding motifs of some other transcription factors were identified in OCT4 binding regions. Our results provide a valuable dataset for understanding gene regulation mechanisms underlying the function of OCT4 in glioblastoma cancer.