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Background: Regulation of alternative splicing is a new therapeutic approach in cancer. The programmed cell death receptor 1 (PD-1) is an immunoinhibitory receptor expressed on immune cells that binds to its ligands, PD-L1 and PD-L2 expressed by cancer cells forming a dominant immune checkpoint pathway in the tumour microenvironment. Targeting this pathway using blocking antibodies (nivolumab and pembrolizumab) is the mainstay of anti-cancer immunotherapies, restoring the function of exhausted T cells. PD-1 is alternatively spliced to form isoforms that are either transmembrane signalling receptors (flPD1) that mediate T cell death by binding to the ligand, PD-L1 or an alternatively spliced, soluble, variant that lacks the transmembrane domain., Methods: We used PCR and western blotting on primary peripheral blood mononuclear cells (PBMCs) and Jurkat T cells, IL-2 ELISA, flow cytometry, co-culture of melanoma and cholangiocarcinoma cells, and bioinformatics analysis and molecular cloning to examine the mechanism of splicing of PD1 and its consequence., Results: The soluble form of PD-1, generated by skipping exon 3 (∆Ex3PD1), was endogenously expressed in PBMCs and T cells and prevents cancer cell-mediated T cell repression. Multiple binding sites of SRSF1 are adjacent to PD-1 exon 3 splicing sites. Overexpression of phosphomimic SRSF1 resulted in preferential expression of flPD1. Inhibition of SRSF1 phosphorylation both by SRPK1 shRNA knockdown and by a selective inhibitor, SPHINX31, resulted in a switch in splicing to ∆Ex3PD1. Cholangiocarcinoma cell-mediated repression of T cell IL-2 expression was reversed by SPHINX31 (equivalent to pembrolizumab)., Conclusions: These results indicate that switching of the splicing decision from flPD1 to ∆Ex3PD1 by targeting SRPK1 could represent a potential novel mechanism of immune checkpoint inhibition in cancer., (© 2023. The Author(s).)

Introduction: Developing approaches for early detection of possible risk clusters for mental health problems among undergraduate university students is warranted to reduce the duration of untreated illness (DUI). However, little is known about indicators of need for care by others. Herein, we aimed to clarify the specific value of study engagement and lifestyle habit variables in predicting potentially high-risk cluster of mental health problems among undergraduate university students., Methods: This cross-sectional study used a web-based demographic questionnaire [the Utrecht Work Engagement Scale for Students (UWES-S-J)] as study engagement scale. Moreover, information regarding life habits such as sleep duration and meal frequency, along with mental health problems such as depression and fatigue were also collected. Students with both mental health problems were classified as high risk. Characteristics of students in the two groups were compared. Univariate logistic regression was performed to identify predictors of membership. Receiver Operating Characteristic (ROC) curve was used to clarify the specific values that differentiated the groups in terms of significant predictors in univariate logistic analysis. Cut-off point was calculated using Youden index. Statistical significance was set at p  < 0.05., Results: A total of 1,644 students were assessed, and 30.1% were classified as high-risk for mental health problems. Significant differences were found between the two groups in terms of sex, age, study engagement, weekday sleep duration, and meal frequency. In the ROC curve, students who had lower study engagement with UWES-S-J score < 37.5 points (sensitivity, 81.5%; specificity, 38.0%), <6 h sleep duration on weekdays (sensitivity, 82.0%; specificity, 24.0%), and < 2.5 times of meals per day (sensitivity, 73.3%; specificity, 35.8%), were more likely to be classified into the high-risk group for mental health problems., Conclusion: Academic staff should detect students who meet these criteria at the earliest and provide mental health support to reduce DUI among undergraduate university students., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ishimaru, Adachi, Mizumoto, Erdelyi, Nagahara, Shirai, Takemura, Takemura, Alizadeh, Higashino, Yagi and Ikeda.)