Citations

T cell exhaustion is often viewed as a terminal state marked by irreversible loss of function during chronic infection and cancer. However, the rapid recovery of antitumor activity in clinical responders after PD-1 blockade suggests that some exhausted T cells retain hidden functional potential. To explain this paradox, we present a theoretical framework that separates latent effector capacity from active effector function. Latent effector capacity represents a history-dependent state reflecting preserved epigenetic accessibility and regulatory readiness, distinct from ongoing gene expression. In this model, PD-1 signaling acts as a reversible mask that suppresses effector function without eliminating the underlying effector capacity. The framework explains preserved chromatin accessibility, rapid reinvigoration after checkpoint blockade, and variable therapeutic responses. By incorporating nonlinear maintenance and erosion of latent effector capacity, the model predicts a bistable system with a point of no return beyond which exhaustion becomes irreversible. These principles may guide development of mechanistically informed biomarkers and artificial intelligence models predicting response to PD-1 therapy.

Background Obstructive sleep apnea (OSA)–chronic obstructive pulmonary disease overlap syndrome has been linked to worse cardiovascular outcomes. Preserved ratio impaired spirometry (PRISm) is recognized as an early stage of chronic obstructive pulmonary diseas. However, whether the coexistence of OSA and PRISm confers increased cardiovascular risk remains unknown. Methods Using data from the Sleep Heart Health Study, participants were categorized into 4 groups according to OSA and PRISm status. The primary outcome was major adverse cardiovascular and cerebrovascular events. The secondary outcome was cardiovascular disease mortality. Multivariable Cox regression models were used to evaluate the association of these groups with the risk of cardiovascular outcomes. Results During a median follow‐up of 11.45 years, the incidence of major adverse cardiovascular and cerebrovascular events was 17.00% in non‐OSA with normal lung function, 27.52% in non‐OSA with PRISm, 25.28% in OSA with normal lung function, and 49.40% in OSA with PRISm. After multivariable adjustment, compared with non‐OSA with normal lung function, the adjusted hazard ratios (HRs) for major adverse cardiovascular and cerebrovascular events were 1.20 (95% CI, 0.82–1.75) in non‐OSA with PRISm, 1.04 (95% CI, 0.89–1.21) in OSA with normal lung function, and 1.52 (95% CI, 1.08–2.12) in OSA with PRISm. Corresponding HRs for CVD mortality were 2.02 (95% CI, 1.26–3.24), 1.05 (95% CI, 0.81–1.35), and 2.17 (95% CI, 1.41–3.34), respectively. A significant sex interaction was observed ( P for interaction=0.009), with the association present only in women. Conclusions The coexistence of OSA and PRISm is independently associated with increased risk of adverse cardiovascular outcomes. This association is observed predominantly in women.

Introduction Spleen tyrosine kinase (SYK) is a non-receptor tyrosine kinase involved in immune signaling and has been implicated in tumor-intrinsic resistance to DNA-damaging therapies. Although SYK activity has been associated with poor outcomes in triple-negative breast cancer (TNBC), its role in resistance to combined radiotherapy and immune checkpoint blockade remains unclear. Methods SYK expression and clinical relevance were assessed across multiple breast cancer cohorts, including radiotherapy-treated datasets. Integrated transcriptomic analyses were used to characterize SYK-associated immune states. The functional effects of pharmacologic SYK inhibition were evaluated using in vitro assays and an immunocompetent bilateral 4T1 tumor model in female BALB/c mice treated with radiotherapy and PD-1 blockade. Treatment-associated immune remodeling was assessed by flow cytometry and transcriptomic profiling. Results Across multiple cohorts, elevated SYK expression, particularly in TNBC, was associated with inferior clinical outcomes and immune dysregulation. Pharmacologic SYK inhibition enhanced tumor responses to radiotherapy and PD-1 blockade at both irradiated and distant tumor sites. These effects were accompanied by coordinated remodeling of the tumor immune microenvironment, including suppression of neutrophil-associated signatures and reductions in immunosuppressive myeloid populations, including M2-like macrophages and myeloid-derived suppressor cells. Discussion Pharmacologic SYK inhibition enhances responses to radiotherapy and PD-1 blockade in preclinical TNBC models and is accompanied by remodeling of the immunosuppressive myeloid compartment. These findings support further investigation of SYK-targeted strategies to improve responses to combined radiotherapy and immune checkpoint blockade.

Abstract Glioblastoma (GBM) remains the most lethal primary brain cancer due to its remarkable metabolic plasticity and therapeutic resistance. Here, we identify cholesterol dependency as a therapeutically exploitable vulnerability in GBM using two FDA-approved drugs: the H1 histamine antagonist clemastine and the retinoid X receptor agonist bexarotene. Combined treatment induces potent synergistic anti-tumor activity across patient-derived glioma models, suppressing proliferation, stemness, and survival at sub-IC50 concentrations. Mechanistically, this therapy disrupts cholesterol biosynthesis, transport, and homeostasis, triggering endoplasmic reticulum stress and activation of the unfolded protein response, ultimately leading to autophagy and apoptotic cell death. Orthotopic patient-derived glioma models recapitulate these mechanisms in vivo, where local intracranial administration significantly reduces tumor progression and prolongs survival using fourfold lower doses than systemic intraperitoneal delivery. Single-cell RNA sequencing revealed activation of regeneration and plasticity programs, accompanied by immune microenvironment remodeling and enhanced inflammatory signaling. Importantly, syngeneic models preserved immune cell composition, supporting future integration with immunotherapeutic strategies. Together, these findings establish cholesterol dysregulation–induced metabolic collapse as a promising therapeutic approach for GBM.

Background Intensive care units are high-acuity environments characterized by time pressure, medical complexity, and organizational demands. These conditions may influence clinicians’ ability to provide patient-centered care and contribute to forms of care perceived as fragmented or dehumanizing. Objective To examine how ICU clinicians describe and make sense of the pressures shaping everyday critical care practice, and how these pressures give rise to interacting patterns of care, including those described as hurry, blur, burden, and cruelty. Methods We conducted a qualitative study using focus groups with ICU clinicians from a large academic health system. Discussions were informed by the concept of the pathologies of care as sensitizing concepts. Four focus groups were held with physicians, nurses, advanced practice nurses, and a social worker ( N = 14). Transcripts were analyzed using directed content analysis with both deductive and inductive coding. Results Clinicians described these patterns not as discrete phenomena but as interrelated, context-dependent processes shaped by shared operational pressures such as time constraints, workload, and information demands. These dynamics were often viewed as inherent to the structure and culture of ICU care and were described as co-occurring and compounding. Communication emerged as both a contributor to and a potential mechanism for mitigation, alongside system-level strategies such as reducing documentation burden and leveraging artificial intelligence to support care delivery. Conclusions Patterns reflected in hurry, blur, burden, and cruelty are best understood as emergent properties of complex care systems. Addressing these dynamics may require system-level approaches to improve communication, reduce workload pressures, and support more patient-centered, humanizing care.

Abstract The liver is organized into tightly regulated zones with distinct metabolic functions but zonation erodes with age. Cellular senescence contributes to aging and liver diseases, however, its impact on aging biology is ill-defined. As part of The Cellular Senescence Network Consortium, we used multiple spatial transcriptomics approaches (GeoMx, Visium, CosMx) with snRNA-seq to profile senescence signatures, zonation markers, and metabolic pathways in livers from wild-type (WT) mice of multiple ages. We observed a loss of canonical zone signatures in aged mouse livers characterized by “expansion” of midlobular (zone 2) marker gene expression, accompanied by diminished expression of zone 3 marker genes by middle-age (18 months), indicative of loss of cell identity. Multiple analytic approaches identified distinct age-, zone- and sex-specific senescence signatures, which were significantly associated with zonation markers changes. This was recapitulated in Ercc1 mutant models of accelerated senescence, supporting a causal role of senescent cells in liver aging. A “no-zone” hepatocyte-like cluster expanded with age and with the strongest Senescence-Associated Secretory Phenotype (SASP) profile. Gene expression profiles from senescent hepatocytes implicate decreased WNT signaling and increased BMP as contributing to age-related loss of zonation. Together, these data elucidate the role of senescent cells in driving aging biology in non-diseased liver through disruption of cell:cell signaling and the loss of metabolic and cell identity gene expression necessary for hepatocyte function.