Alterations of ocular surface parameters in patients with obstructive sleep apnea syndrome

PurposeThis study aimed to evaluate changes in ocular surface parameters among obstructive sleep apnea syndrome (OSAS) patients.Methods44 healthy volunteers (88 eyes) and 27 OSAS patients (54 eyes) were recruited in our cross-sectional study. 14 patients were classified as mild&moderate OSAS, and 13 patients were classified as severe OSAS. For evaluating the ocular surface, the following tests were conducted: the height of tear meniscus (TMH), first non-invasive tear break-up time (FNITBUT), mean non-invasive tear break-up time (MNITBUT), the score of Meibomian gland dropout area (Meiboscore), the tear test of anesthesia-free Schirmer I (SIT), corneal fluorescein staining (CFS), partial blinks rate (PBR), the lipid layer thickness (LLT), ocular surface disease index (OSDI). The results obtained from the study were analyzed and compared among the groups.ResultsFNITBUT, MNITBUT, and TMH were lower. OSDI, CFS, Meiboscore and PBR were higher in the OSAS group than those in the control group. The mild&moderate as well as the severe OSAS subgroups had statistically significantly lower TMH, and higher OSDI and PBR than the control group. Meanwhile, we found there were no significant differences between two OSAS subgroups. CFS was higher in the severe OSAS group than the mild&moderate OSAS group. Significantly lower FNITBUT, MNITBUT and higher Meiboscore were observed in the severe OSAS subgroup than in the control group, and MNITBUT was higher in severe OSAS objects than in the mild&moderate OSAS objects. LLT and SIT did not exhibit significant differences among control and OSAS subgroups. FNITBUT and MNITBUT showed significantly negative correlations with BMI, while Meiboscore showed a significant positive correlation with AHI.ConclusionPatients with OSAS have a tendence of dry eyes, whereas control subjects do not. This indicates us that the OSAS patients should pay more attention to ocular surface care

Identification of a small molecule Tim-3 inhibitor to potentiate T cell-mediated antitumor immunotherapy in preclinical models

<p><span>T cell immunoglobulin and mucin-containing molecule 3 (Tim-3), expressed in dysfunctional and exhausted T cells, has been widely acknowledged as a promising immune checkpoint target for tumor immunotherapy. Here, using a strategy combining virtual and functional screening, we identified a compound named ML-T7 that targets the FG-CC' cleft of Tim-3, a highly conserved binding site of </span><span>phosphatidylserine</span><span> (PtdSer) and carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1). ML-T7 enhanced the survival and antitumor activity of </span><span>primary CD8<sup>+</sup> cytotoxic T lymphocytes (CTLs) and human chimeric antigen receptor (CAR) T cells and reduced their exhaustion </span><span>in vitro and in vivo</span><span>. In addition, ML-T7 promoted NK cells' killing activity and DC antigen-presenting capacity, consistent with the reported activity of Tim-3.</span><span> Notably, ML-T7 strengthened DCs' functions through both Tim-3 and Tim-4, consistent with the hypothesis that Tim-4 contains a similar FG-CC' loop. Intraperitoneal dosing of ML-T7 showed comparable tumor inhibitory effects to Tim-3 blocking antibody. ML-T7 reduced syngeneic tumor progression in both wildtype and Tim-3 humanized mice and alleviated the immunosuppressive microenvironment. Furthermore, combined ML-T7 and anti-PD-1 therapy had greater therapeutic efficacy than monotherapy in mice, supporting further development of ML-T7 for tumor immunotherapy. Our study demonstrates a potential small molecule for selectively blocking Tim-3 and warrants further study.</span></p><p>Funding provided by: National Natural Science Foundation of China<br>Crossref Funder Registry ID: https://ror.org/01h0zpd94<br>Award Number: 81830017</p><p>Funding provided by: National Natural Science Foundation of China<br>Crossref Funder Registry ID: https://ror.org/01h0zpd94<br>Award Number: 31600714</p><p>Funding provided by: National Natural Science Foundation of China<br>Crossref Funder Registry ID: https://ror.org/01h0zpd94<br>Award Number: 81903454</p><p>Funding provided by: National Postdoctoral Program for Innovative Talents<br>Award Number: BX201700147</p><p>Funding provided by: Young Elite Scientist Sponsorship Program by CAST<br>Award Number: YESS20160077</p><p>Funding provided by: Taishan Scholarship<br>Award Number: 20181201</p><p>Funding provided by: Shandong Natural Science Foundation<br>Crossref Funder Registry ID: http://dx.doi.org/10.13039/501100007129<br>Award Number: ZR2020ZD12</p><p>Funding provided by: National Key Research and Development Program<br>Crossref Funder Registry ID: http://dx.doi.org/10.13039/501100012166<br>Award Number: 2021YFC2300603</p><p>Splenocytes from OT-Ι mice were stimulated with 10 nM OVA<sub>257-264</sub> peptide in RPMI 1640 medium containing 10% FBS, 50 U/mL penicillin-streptomycin, 50 μM 2-Mercaptoethanol, 20 U/mL human recombinant IL-2 and 10 μM ML-T7/DMSO for 3 days, followed by 3 days culture in the presence of ML-T7/DMSO to get mature CTLs unless otherwise indicated.Total RNA was isolated from DMSO or ML-T7 treated CD8<sup>+</sup> CTLs using TRIzol reagent (Invitrogen). RNA-Seq analysis was performed with an Illumina HiSeq 2500 or BGISEQ-500 by BGI (Shenzhen, Guangdong, China). Data quality was assessed with fastqc software and aligned to the mouse genome (mm10 build) using TopHat (with Bowtie2), and data was curated and visualized using the BGI Interactive analysis platform.RNAseq detected 1271 differentially expressed transcripts (1.5-fold or more) in ML-T7-treated CD8<sup>+</sup> CTLs. Specifically, ML-T7 treatment upregulated several effector T cell-associated genes, including <em>Lck</em>, <em>Zap70</em>, <em>Erk1</em>, <em>Il-2</em> and <em>Cd69</em>, while downregulated several exhausted T cell-associated genes, including <em>Havcr2, Tigit</em> and <em>Ctla4</em>. Gene set enrichment analysis (GSEA) showed that TCR signaling pathway and IL2-STAT5 pathway were significantly enriched in ML-T7-treated CTLs.</p&gt