Citations

Background: Sleep is vital for an athlete’s recovery, physical and mental health, and athletic performance. The impact on circadian rhythm from long-distance travel across multiple time zones has not been studied using wearable technology in female professional tennis players. Hypothesis: Travel between time zones in female professional tennis players leads to circadian desynchronization, causing disruption in sleep patterns, changes in physiologic parameters, and decreased athletic performance. Study Design: Retrospective cohort study. Level of Evidence: Level 3. Methods: A total of 52 female professional tennis players consented to wear, and share the data of, WHOOP 3.0 while traveling and competing on the Women’s Tennis Association (WTA) Tour. Linear mixed models examined the relationship between (1) travel and sleep/recovery and (2) sleep/recovery and match performance. Results: Sleep duration without travel averaged 437 minutes (436.8 ± 2.8). On the first night after travel, for every hour time zone difference (TZD) traveled regardless of direction, players slept 11 minutes less (−11.3 ± 0.96; P < 0.05). Eastward travel further reduced sleep (−24.5 ± 4.2; P < 0.05), while westward travel increased sleep duration (+30.0 ± 4.2; P < 0.05). These effects were reduced on the subsequent 2 nights. Conclusion: Sleep duration reduction was most prominent on the first night after travel, particularly with eastward travel, but improved on subsequent nights. The number of time zones crossed predictably increases the vulnerability for insufficient sleep duration, whereby a 2-hour TZD easterly, and 4-hour TZD westerly, reduces sleep duration <7 hours on the first night. No significant correlation was found between sleep disruption and competition performance in our female professional tennis population. Clinical Relevance: The findings suggest that professional tennis players should, and generally do, arrive at competition locations with enough time to resynchronize their circadian rhythm to the destination time zone; particularly if traveling eastward.

Abstract Description Interactions between ST6GAL1-produced sialic acids and Siglec-2 (CD22) result in immune inactivation. CD22 is a well-characterized regulator of B cell function. We demonstrate that conventional type-2 dendritic cells (cDC2s) and hybrid macrophages express CD22 across the spleen and tumor microenvironment. To understand the function of CD22 on antigen-presenting cells, we generated novel CD22-floxed mice and crossed them with a) Zbtb46-Cre ones (those lacking CD22 on cDC2s and hybrid macrophages) as well as b) CX3CR1-Cre mice (without CD22 on hybrid macrophages nor microglia). From the former cross, we generated subcutaneous flank tumor and colitis-associated colorectal cancer models. CD22 expression on myeloid cells did not impact anti-tumor responses when tumors expressed low CD22 ligand levels. From here, we assess the impact of tumor cell CD22 ligand overexpression on tumor responses. Also, to evaluate CD8 T cell response to CD22, we challenged mice with Theiler’s murine encephalomyelitis virus (TMEV), modeling multiple sclerosis via CD8 T cell hyperactivation. CD22 did not mediate CD8 activation nor infiltration in brains of the latter cross. Thus, CD22 may be functionally redundant across myeloid and B cells. Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)

Abstract Description Generation of T cells requires dynamic epigenetic alteration of histones to control gene expression at each developmental stage. The Class I deacetylases HDAC1, HDAC2, and HDAC3 have been shown to have 3 functions: adaptor, decrotonylase, and deacetylase activity. The relative importance of each function in T cells is not known. CD2icre HDAC3 cKO mice develop severe colitis and demonstrate that HDAC3 is required during thymocyte development for positive selection, DP survival, and CD4 lineage commitment. Recently, a mutation was identified in HDAC3 that eradicated deacetylase activity (“VRPP”). We generated a novel mouse model with Cre-mediated deletion of endogenous HDAC3 and linked re-expression of HDAC3 VRPP, which maintained adaptor function but lacks both deacetylase and decrotonylase enzymatic activity. Similar to CD2icre HDAC3 cKO mice, HDAC3 VRPP mice have a block in positive selection due to failure to down regulate RORγt and decreased DP cell survival due to increased expression of P2RX7, demonstrating that HDAC3 enzymatic activity is required for these functions. However, when the positive selection defect is bypassed in HDAC3 VRPP mice, CD4+ lineage commitment is restored. Strikingly, this mouse does not develop spontaneous colitis even up to one year of age, although T cell development is still impaired. Thus, there are different roles for HDAC3 enzymatic vs. adaptor function during T cell development which are made evident in HDAC3 VRPP mice. Funding Sources NIAID RO1 AI150100; T32 AI170478; Mayo Clinic Graduate School of Biomedical Sciences Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)

Abstract Description B7-H3 is a member of the B7 superfamily, which includes co-inhibitory receptors such as B7-H1/PD-L1 and co-stimulatory receptors such as B7-1/CD80 and B7-2/CD86. B7-H3 is upregulated by almost all types of tumors and is associated with worse prognosis. However, the exact mechanism by which B7-H3 suppresses anti-tumor immune response remains to be discovered as its ligand has yet to be identified. Sialic acid modifications are also increased in many cancers and are similarly associated with poor outcome. Here, we demonstrate for the first time that sialylated B7-H3 binds to the immune inhibitory receptor Siglec-9. Siglec-9 is expressed on many immune cells, including NK cells and T cells. We have shown that B7-H3 expression on target cells reduces killing by Siglec-9 expressing NK cells in vitro. We then hypothesized that antibodies that block B7-H3 binding to Siglec-9 will be an effective intervention to boost anti-tumor immunity. We have generated a high affinity anti-B7-H3 monoclonal antibody, F7, which blocks B7-H3 binding to Siglec-9. F7 functions to enhance NK cell killing of B7-H3 expressing target cells in vitro. F7 also dramatically enhances CART19 mediated killing of B7-H3 expressing Nalm6 cells in a relapse model in NSG mice in vivo. In summary, our work has demonstrated that B7-H3 binds Siglec-9, and blockade of such interaction can enhance anti-tumor immunity. Funding Sources • Mayo Clinic Center for Biomedical Discovery • NIH Glycobiology Common Fund supplement to R01CA243545-01A1 to VSS Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)

Abstract DAB2IP (Disabled homolog 2 interacting protein), a recognized tumor suppressor, plays a pivotal role in regulating various oncogenic pathways. Our previous research demonstrated that DAB2IP functions as a cell cycle regulator by facilitating PLK1-mediated mitosis progression. Here, we elucidate a novel function of DAB2IP in promoting DNA replication origin firing. Mechanistically, we identified that DAB2IP localizes to the nucleus, where it interacts with the histone acetyltransferase HBO1 and enhances the HBO1–PLK1 interaction. DAB2IP facilitates PLK1-mediated phosphorylation of HBO1, which subsequently promotes HBO1-directed acetylation of histone 3 at lysine 14 (H3K14Ac). This modification enables the loading of the minichromosome maintenance protein (MCM) complex onto chromatin, thereby supporting DNA replication and maintaining genome integrity. Additionally, we found that ATR regulates CDK1-mediated phosphorylation of DAB2IP, and that this phosphorylation is essential for the formation and activation of the HBO1-PLK1 complex. Ablation of DAB2IP phosphorylation results in increased genomic instability due to incomplete replication of genomic DNA, as evidenced by the accumulation of anaphase ultrafine bridges and 53BP1 nuclear bodies in G1 phase of the cell cycle. In summary, our findings underscore the critical regulatory role of DAB2IP in DNA replication initiation and genomic stability maintenance, providing new insights into its function in cellular homeostasis.

OBJECTIVE Hundreds of thousands of Americans undergo decompression for lumbar spinal stenosis annually. The mild (minimally invasive lumbar decompression) procedure was developed as a potentially less invasive alternative to open decompression; however, much of the evidence has been gathered from industry-sponsored studies. The present study sought to compare real-world clinical outcomes between the mild procedure and open decompression for lumbar spinal stenosis. METHODS All patients who underwent the mild procedure at a single-institution, multisite, tertiary care center from 2005 to October 2024 were included. One-to-one propensity score matching was used to identify patients who underwent open decompression at the same institution, with age, sex, smoking, and comorbidities as covariates. Primary outcomes were change in pain on the numeric rating scale (NRS), surgical reoperation, and perioperative complications. For pain, the minimal clinically important difference (MCID) was defined as a 30% improvement in NRS score. RESULTS A total of 175 patients who underwent the mild procedure (mean age 76.3 ± 8.7 years; 44.6% female) were matched to 175 patients treated with open decompression (mean age 75.4 ± 8.7 years; 44.0% female). Among patients with at least 60 days of follow-up, those treated with open decompression were more likely to achieve the MCID for pain (43.1% vs 22.2%, p < 0.001). Patients treated with mild were more likely to require reoperation (46.2% vs 29.3%, p = 0.008). Those who underwent the mild procedure experienced lower rates of durotomies (0% vs 2.9%, p = 0.024) but had higher rates of neurological deficits (6.3% vs 0.6%, p = 0.003). CONCLUSIONS For patients with symptomatic lumbar stenosis, those who underwent open decompression were more likely to achieve pain improvement and less likely to require reoperation compared with those who underwent the mild procedure.