Citations

Abstract Purpose It remains unclear whether increasing the frequency of administration of 0.01% atropine improves its effectiveness in slowing axial elongation or refractive progression. This study compared twice‐daily 0.01% atropine administration and traditional once‐nightly administration. Methods A hybrid design was adopted incorporating both retrospective and prospective elements, with participants observed for 1 year. The control group (received saline eye drops) and once‐daily 0.01% atropine group (Atropine‐1 group) were derived from two previous trials, while the twice‐daily 0.01% atropine group (Atropine‐2 group) was enrolled prospectively. A total of 163 participants were included in the intention‐to‐treat set, with 51, 70 and 42 participants in the control, Atropine‐1 and Atropine‐2 groups, respectively. The primary outcome was the change in axial length (AL), and the secondary outcome was the change in cycloplegic spherical equivalent refraction (SER). Results Compared with the control group (0.48 ± 0.22 mm), both Atropine‐1 (0.26 ± 0.17 mm) and Atropine‐2 (0.15 ± 0.18 mm) groups showed significantly reduced AL elongation ( p < 0.001). Notably, Atropine‐2 significantly improved slowing of AL elongation compared with Atropine‐1 ( p = 0.008). The result of the secondary outcome (adjusted SER change) was consistent. Atropine‐2 was significantly more effective in slowing SER progression (−0.15 ± 0.37 D) than Atropine‐1 (−0.41 ± 0.50 D) ( p = 0.02). Based on a multivariable model, age was identified as the key covariate to perform subgroup analyses. In the younger subgroup (8–10 years), AL elongation was significantly reduced in the Atropine‐2 group (0.16 ± 0.17 mm) compared with the Atropine‐1 group (0.36 ± 0.22 mm; p = 0.002). In the older subgroup (10–12 years), there was no significant difference in progression. Consistent results were observed in the sensitivity analyses based on the per‐protocol set. Conclusion Twice‐daily administration of 0.01% atropine was more effective than once daily in slowing AL elongation and SER progression in children 8 to 10 years of age. Further investigation with extended follow‐up is warranted to substantiate this finding.

Introduction In moderate to high-risk surgical procedures, 15–25% of patients develop a postoperative surgical site infection. Intraoperative incisional wound irrigation has the potential to reduce surgical site infections, and additional randomised controlled trials are required to provide evidence of effectiveness. Methods and analysis This protocol describes a pragmatic, adaptive, participant and adjudicator-blinded trial at 13 sites in Canada in up to 2500 participants. Participants planned for surgery with an abdominal or groin incision, who are eligible and provide verbal consent through an integrated consent model, are randomised to receive intraoperative incisional wound irrigation with povidone-iodine, saline or no irrigation. The primary outcome is surgical site infection within 30 days postoperatively. Secondary outcomes include quality of life measured 30 days postoperatively and morbidity, mortality and healthcare utilisation within 90 days postoperatively. Ethics and dissemination This trial has been approved by the research ethics board at the participating centres and stopped enrolling participants on May 23, 2025. All participants will provide verbal consent. Results will be disseminated via presentation at conferences, publication and posted on clinicaltrials.gov. Trial registration number The study is registered with http://clinicaltrial.gov ( NCT04548661 ; 14 September 2020).

ABSTRACT Knowledge of Treponema pallidum subspecies pallidum ( TPA ) outer membrane protein (OMP) sequence variability is essential for understanding spirochete proliferation within endemic populations as well as the design of a globally effective syphilis vaccine. Our group has identified extracellular loops (ECLs) of TPA BamA (TP0326) and members of the FadL family (TP0548, TP0856, TP0858, TP0859, and TP0865) as potential components of a multivalent vaccine cocktail. As part of a consortium to explore TPA strain diversity, we mapped the variability of BamA and FadL orthologs in 186 TPA strains from Malawi, China, and Colombia onto predicted 3D structures. The 186 genomes fell into eight subclades (five Nichols- and three SS14-lineage) with substantial geographic restriction. Single nucleotide variants accounted for the large majority of proteoforms, with variability notably higher within the Nichols-lineage strains. Most mutations were in regions of the proteins predicted to be extracellular and harboring B cell epitopes. We observed a striking difference in the degree of variability between the six OMPs, suggesting that these proteins are following divergent evolutionary paths. Concatenation of OMP sequences recapitulated the phylogenetic structure of the TPA strains, effectively segregating within clades and largely clustering by subclades. Finally, we noted that BamA and FadL candidate ECL vaccinogens, previously shown to elicit antibodies that kill treponemes during in vitro cultivation, are well conserved. Taken as a whole, our study establishes a structural-phylogenetic approach for analyzing the forces shaping the host-pathogen interface in syphilis within endemic populations while informing the selection of vaccine targets. IMPORTANCE Syphilis remains a major global health concern, reinforcing the need for a safe and effective vaccine. Understanding the variability of TPA OMPs is essential for tracking pathogen evolution and informing vaccine design. Here, we analyzed the variability of six TPA OMPs in 186 strains from Malawi, China, and Colombia, identifying protein-specific evolutionary patterns. Most mutations were localized in extracellular regions and, notably, appeared to correlate with the phylogenetic structure of TPA . Despite OMP heterogeneity, several candidate vaccinogens remained highly conserved, reinforcing their potential as globally effective vaccine targets. Our study establishes a structural-phylogenetic framework for dissecting the forces shaping the host-spirochete interface within endemic populations and provides a foundation for designing a globally effective syphilis vaccine.

Abstract Introduction: Radiotherapy (RT)-induced acute esophagitis (AE) is a common side effect in lung cancer patients receiving RT, which can significantly impact their quality of life. This highlights the need for a predictive model that can estimate AE risk in advance using pretreatment imaging data. However, collecting sufficient data for model development is often resource-intensive and costly. Additionally, acquiring a homogeneous training dataset (e.g., from a single center or modality) is not always feasible. This study aimed to develop an automated artificial intelligence-based 3D vision foundation model (VFM) combining standard-of-care planning computed tomography (pCT) and planned radiation dose maps to predict grade II or higher AE. Materials and methods: This study included 246 patients with non-small cell lung cancer who underwent either image-guided radiation treatment (IMRT) or proton-beam radiation therapy. The endpoint was grade two or higher AE (33% positive and 67% negative). The IMRT group consisted of 182 patients from a single center, whereas the proton therapy group included 64 patients from the Proton Collaborative Group trial from 11 different institutions. For each patient, pCT, dose maps, and radiotherapy segmentations were available. The VFM was created using a transformer pretrained using a large number of unlabeled volumetric 3D CTs from patients with varied diseases through a self-supervised learning approach, which extracts useful features directly from images. Next, the pretrained encoder was combined with fully connected classification layers and fine-tuned using stratified 5-fold cross-validation with 20 patients set aside for testing. We developed two models: a CT only and CT + dose model. Model performance was assessed using the area under the curve (AUC), specificity, and sensitivity. Results: In cross-validation, adding dose information to CT (CT+Dose) improved model performance, increasing AUC from 0.72 ± 0.08 to 0.76 ± 0.10 and specificity from 0.82 ± 0.09 to 0.87 ± 0.04, while sensitivity remained the same. On the independent test set, CT+Dose showed a marked improvement over CT only (AUC: 0.82 vs. 0.59; sensitivity: 0.57 vs. 0.14), with a slight decrease in specificity (0.77 vs. 1.00). Conclusion: A VFM model combining CT and radiation dose showed the capability to predict AE more accurately with higher specificity. Further studies on larger cohorts of testing patients are planned to assess model generalization. Citation Format: Chloe Min Seo Choi, Jue Jiang, Nikhil Mankuzhy, John Chang, Jing Zeng, Carlos Vargas, James Urbanic, Isabella Choi, Mark Mcdonald, James Gray, Joseph Deasy, Maria Thor, Charles Simone, Harini Veeraraghavan. Prediction of radiotherapy-Induced esophagitis in non-small cell lung cancer using a 3D vision foundation model [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Artificial Intelligence and Machine Learning; 2025 Jul 10-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(13_Suppl):Abstract nr B022.

CDK12 primarily functions as a transcription regulatory cyclin-dependent kinase (CDK) that controls mRNA elongation, splicing, and polyadenylation. The CDK12 gene is implicated in human cancers since it is frequently mutated and/or deleted in prostate and ovarian cancer but paradoxically amplified in breast cancer. Here, we demonstrate that CDK12 promotes serine-933 phosphorylation of DNA2, a nuclease/helicase critical for replication fork stress regulation, and the phosphorylation subsequently facilitates DNA2 polyubiquitination and degradation mediated by the APC/C CDC20 E3 ubiquitin ligase. CDK12 inactivation induces but amplification suppresses genome-wide expression of interferon response and antigen processing and presentation machinery genes in ovarian and breast cancer cells, respectively. Besides causing aberrant DNA2 stabilization, replication stress, genomic instability, and cytosolic double-stranded DNA (dsDNA) accumulation, CDK12 loss also triggers cGAS–STING activation and innate immune response, which can be reversed by forced expression of replication protein A (RPA) subunits or DNA2 depletion. Our findings identify DNA2 as a phosphorylation substrate of CDK12, connecting CDK12 to cell cycle regulation. These data also reveal DNA2 protein destruction as a critical mechanism that dictates genomic instability, cGAS–STING signaling activation, and innate immune response in CDK12-deregulated cancers.

Oncogene expression can cause replication stress (RS), leading to DNA double-strand breaks (DSBs) that require repair through pathways such as homologous recombination, nonhomologous end-joining, and microhomology-mediated end-joining (MMEJ). Cyclin D1 (encoded by CCND1 ) is a well-known oncoprotein overexpressed in cancer; however, its role in RS is unknown. Using mantle cell lymphoma (MCL) as a naturally occurring model of cyclin D1 overexpression, we examined the impact of cyclin D1 on RS and DSB repair mechanisms. Cyclin D1 overexpression elevated RS, increased DNA damage, especially during mitosis, and caused specific upregulation of MMEJ. Furthermore, cyclin D1 activated polymerase theta ( POLQ ) transcription by binding its promoter loci, driving POLΘ-mediated MMEJ that is essential to withstand cyclin D1–induced RS. Moreover, concurrent ATM deficiency further intensified RS, enhanced POLQ expression, and heightened reliance on MMEJ-mediated DNA damage repair. Consequently, inhibition of POLΘ in cyclin D1–overexpressed settings further exacerbated RS, causing single-strand DNA gap accumulations and chromosomal instability, ultimately leading to apoptosis, an effect amplified in ATM-deficient cells. Targeting MMEJ via POLΘ inhibition is therefore an effective strategy in the context of cyclin D1 overexpression and ATM deficiency and may provide a unique therapeutic approach for treating MCL and other malignancies characterized by similar alterations.

Summary Dupilumab, the first biologic approved for eosinophilic esophagitis treatment (EoE-tx) in 2022, demonstrated favorable safety in phase-III clinical trials. However, real-world dupilumab-associated adverse reactions (DARs) for EoE-tx are unknown. This study aims to evaluate DAR for EoE-tx using the FDA Adverse Event Reporting System. FDA Adverse Event Reporting System was queried for DAR between 2022Q1 and 2023Q4. Individual DARs (iDARs) were categorized and compared between treatment groups: EoE, asthma, atopic dermatitis, and chronic rhinosinusitis with nasal polyps. Logistic regression was used to predict serious DAR and outcomes, and zero-truncated negative binomial regression was used to predict the number of iDAR. There were 51,000 DAR observations; 1459 for EoE-tx with 103 (7.1%) serious reactions and 44 (3.0%) serious outcomes including 3 deaths. For EoE-tx, the mean iDAR was 3.68 [3.51, 3.85], and the iDAR incidence rate ratio among men receiving EoE-tx was 0.73 [0.65, 0.83]. EoE-tx average iDAR primarily included general (0.75 [0.70, 0.80]), injection-site (0.69 [0.63, 0.74]), dermatologic (0.51 [0.46, 0.55]), and gastrointestinal (0.24 [0.21, 0.27]) reactions. Adults ≥50 years had 1.97 [1.28, 2.99] higher odds for serious DAR compared to younger adults in EoE-tx. Overall, dupilumab demonstrated a favorable safety profile across all indications, with low rates of serious adverse events. For EoE-tx specifically, higher total iDAR rates were observed, driven largely by increased injection-site and gastrointestinal reactions compared to other indications. Additionally, women exhibited higher iDAR rates than men across all indications.

Abstract Cerium oxide (CeO 2 ) nanozymes have emerged as a novel class of nanozyme materials distinguished by their tunable valence states (Ce 3+ /Ce 4+ ) and abundant surface oxygen vacancies (OVs), demonstrating exceptional chemical stability, cost‐effectiveness, and scalable manufacturability. Precise control of reaction temperature or implementation of carrier‐mediated crystal growth strategies effectively enhances nanoparticle dispersion and mitigates aggregation. This review systematically summarizes recent advancements in CeO 2 nanozymes: First, it elaborates on cutting‐edge synthetic methodologies, encompassing self‐supported strategies (calcination, hydrothermal, and sol–gel) and carrier‐mediated approaches (small‐molecule compounds, macromolecular compounds, and nanomaterials), with comparative analysis of their respective merits and limitations. Second, the catalytic mechanism is comprehensively elucidated, particularly focusing on the modulation of electron transfer kinetics and surface adsorption energies in metal/nonmetal hybrid systems. By optimizing oxygen vacancy concentration to regulate Ce 3+ /Ce 4+ redox cycling dynamics, significant enhancement in redox efficiency and catalytic stability can be achieved, enabling precise enzyme‐like activity regulation. Furthermore, the review comprehensively summarizes breakthrough applications in multidimensional biomedical fields, including precision tumor therapy, intelligent antibacterial systems, inflammatory microenvironment regulation, and ultrasensitive biosensing. This work establishes a theoretical framework for structure‐activity relationship‐guided rational design of high‐performance CeO 2 nanozymes and delineates their potential translational applications in precision medicine.