Citations

While most cases of human muscle-invasive bladder cancer (MIBC) are diagnosed as conventional urothelial carcinoma (UC), there is growing recognition of histologic subtypes and divergent differentiation within conventional UC. In this study, 31 dogs with UC (33 slides) were evaluated for histologic subtypes and divergent differentiation, as specified by the recent World Health Organization update on the classification of urinary bladder cancers. Slides were reviewed by a medical uropathologist and 3 board-certified veterinary pathologists and assessed for expression of uroplakin III, vimentin, and E-cadherin. All tumors were classified as UC. Fifteen cases were identified as conventional UC. Among the remainder, 8 displayed glandular differentiation, 4 were classified as sarcomatoid UC, 2 showed squamous differentiation, 1 case was classified as a large nested subtype, and 1 case was classified as a tubular/microcystic subtype. This study found a higher frequency of certain histologic subtypes and divergent differentiation in canine UC, particularly sarcomatoid UC and UC with glandular differentiation, compared to previous reports of both canine UC and human MIBC. The relatively high prevalence of the sarcomatoid UC and UC with glandular differentiation in dogs observed in this study suggests that canine UC may serve as a valuable translational model for evaluating novel therapeutic agents, particularly for these rare and aggressive subtypes in humans.

Abstract Neuromodulatory subcortical systems (NSSs) are uniquely susceptible to dementia‐related pathology, leading to frequent molecular and behavioral impairments associated with altered function of these nuclei. Some of these systems display clear sex‐specific cytoarchitecture and signaling leading to distinct physiology and behavioral outputs in males and females, while other regions display nominal sex differences. However, the relevance of sex differences in modulating dysfunction of NSSs in Alzheimer's disease (AD) and related dementias is not well understood. This review is a joint effort by the Neuromodulatory Subcortical Systems and Sex and Gender Differences in Alzheimer's Disease Professional Interest Areas of the Alzheimer's Association. We review sex differences in NSSs, both in non‐disease states and in AD models and patients. We highlight the possible role of NSSs in driving sex‐specific AD susceptibility and potential footholds for sex‐based interventions targeting these systems. We conclude by outlining immediate and long‐term actions to address the intersection of NSSs, sex, and AD.

ABSTRACT Background and Aims Women now comprise over half of US medical school matriculants yet remain underrepresented in academic leadership, including emergency medicine (EM). Leadership training within medical education is variable, particularly in communication, conflict management, negotiation, and operations. Concurrently, large language models (LLMs) are emerging as accessible tools to support leadership skill development. This study aimed to develop and evaluate an AI‐augmented leadership skills workshop designed to address the leadership gap for women in academic emergency medicine. Materials and Methods The Academy for Women in Academic Emergency Medicine (AWAEM) developed and piloted a leadership development workshop at the 2025 Society for Academic Emergency Medicine Annual Meeting. The curriculum integrated evidence‐based leadership frameworks with experiential small‐group learning and structured demonstrations of LLM use. Educational strategies included brief didactics, reflection on lived leadership challenges, peer discussion, and guided LLM‐supported simulation of leadership conversations. Pre‐workshop and postworkshop surveys and qualitative feedback were collected to assess participant confidence and perceived utility. Results Participants demonstrated increased confidence in navigating power‐differential conversations and initiating negotiations following the workshop. There was greater reported intent to apply leadership frameworks and to utilize LLMs for leadership‐related tasks. Qualitative feedback highlighted themes of empowerment, practical applicability, and the importance of a psychologically safe, gender‐informed learning environment. Participants identified LLMs as a novel and accessible adjunct to traditional leadership development resources. Discussion and Conclusions An AI‐augmented, experiential leadership workshop is a feasible and scalable approach to addressing persistent leadership development gaps for women in academic emergency medicine. Integrating LLM‐supported practice with established leadership frameworks may enhance learner confidence and engagement. This model offers a practical strategy to support leadership skills for women physicians needed to navigate systemic barriers and advance into leadership roles.

In this study, we propose two new mathematical models able to quantify glucagon secretion during a graded glucose infusion, in the presence and absence of amino acids. The models provide an index of α-cell responsivity, G 50 , i.e., the glucose increase required to suppress glucose secretion rate (GSR) by 50%. Results show that the presence of amino acids reduced α-cell responsivity to glucose.

IMPORTANCE Neoadjuvant chemoimmunotherapy has high rates of pathologic response and improved prognosis among solid tumors. Its role in head and neck squamous cell carcinoma (HNSCC) remains understudied. OBJECTIVE To summarize the efficacy associated with neoadjuvant chemoimmunotherapy regimens in HNSCC and to compare the efficacy associated with neoadjuvant chemoimmunotherapy vs immunotherapy alone in locoregionally advanced resectable HNSCC prior to definitive surgery. DATA SOURCES A librarian-led systematic review was conducted using multiple electronic databases, including Medline, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus, following Preferred Reporting Items for Systematic Reviews and Meta- Analyses (PRISMA) guidelines. Databases were queried from inception to October 2024. STUDY SELECTION Inclusion criteria included prospective interventional trials that have completed accrual, with results published in English. Only trials of resectable, treatment-naive HNSCC were included. Exclusion criteria included lack of reporting on pathologic response or Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 response. DATA EXTRACTION AND SYNTHESIS Two investigators independently conducted title, abstract, and full-text reviews per PRISMA guidelines. Primary outcomes extracted were major pathologic response (MPR) and complete pathologic response (CPR) at surgery and complete response (CR) on imaging by RECIST 1.1. Secondary outcomes included 1-year overall survival (OS) and toxic effects. MAIN OUTCOMES AND MEASURES A meta-analysis was performed using a binary random-effects model to determine the pooled proportion of primary outcomes in the immunotherapy and chemoimmunotherapy groups. Heterogeneity was reported as I 2 . RESULTS A total of 751 patients (502 [77%] male; age range, 27-87 years) across 23 studies were included in the meta-analysis, including 357 patients (47%) who underwent chemoimmunotherapy, 102 patients (14%) who underwent dual-agent immunotherapy, and 292 patients (39%) who underwent single-agent immunotherapy. Pooled rates of MPR plus CPR were 66% (95% CI, 58%-73%; I 2 = 0.59) for chemoimmunotherapy, 18% (95% CI, 6%-29%; I 2 = 0.65) for dual-agent immunotherapy, and 6% (95% CI, 3%-9%; I 2 < 0.01) for single-agent immunotherapy. Across all groups, 1-year OS rates ranged from 88% to 96% for single-agent immunotherapy, 88% to 96% for dual-agent immunotherapy, and 88% to 100% for chemoimmunotherapy. Grade 3 to 5 adverse events were reported in 61 of 210 patients (29%), 2 of 67 patients (3.0%), and 36 of 210 patients (17%) among the reporting studies in the single-agent immunotherapy, dual-agent immunotherapy, and chemoimmunotherapy groups, respectively. CONCLUSIONS AND RELEVANCE These findings suggest that neoadjuvant chemoimmunotherapy regimens were associated with higher pathologic and radiographic response rates compared with immunotherapy alone in locoregionally advanced HNSCC. These results call for phase 3 trials comparing these neoadjuvant regimens head to head.

Abstract The recent FDA approval of the first T-cell receptor–engineered (TCR) T-cell cancer therapy has solidified the treatment as a viable therapeutic strategy. However, only a fraction of patients who received this treatment achieved substantial and long-lasting responses, highlighting the need to understand the molecular underpinnings of these responses and develop more effective strategies to improve this therapy. Previous research has demonstrated that the activation of myeloid differentiation primary response 88 (MyD88) signaling in tumor-specific T cells functions as a robust costimulatory signaling pathway that promotes effective antitumor T-cell responses. In this study, we developed a strategy for improving TCR T-cell therapies by creating a synthetic TCR in which the intracellular domain of CD3ζ and a modified MyD88 are appended to the β-chain of a tumor-reactive TCR. The β:CD3ζ:MyD88 TCR activated MyD88 signaling in a tumor antigen/TCR-specific manner, and β:CD3ζ:MyD88 TCR T cells exhibited enhanced functionality and a reduced propensity to become exhausted. Furthermore, MyD88 signaling promoted T-cell persistence and expansion in vitro. In vivo, tumor-infiltrating β:CD3ζ:MyD88 TCR T cells skewed the immunosuppressive tumor microenvironment toward a less immunosuppressive state. Finally, β:CD3ζ:MyD88 TCR T cells substantially delayed tumor growth kinetics in a melanoma model. These findings introduce an approach for improving TCR-dependent T-cell responses by directly appending signaling domains to the full-length TCR and exemplify the utility of activating MyD88 signaling in tumor-specific T cells. Significance: A chimeric β:CD3ζ:MyD88 TCR reduces exhaustion and improves antitumor T-cell responses, overcoming the limited efficacy of current TCR-engineered T-cell cancer therapies.