Citations

Immune checkpoint inhibitors (ICIs) can cause immune-related adverse events (irAEs), with acute interstitial nephritis (ICI-AIN) being the most common irAE. While the exact mechanism remains unclear, upregulation of IFN-γ and TNF-α pathways has been implicated. This study used a humanized chimeric PD-1/PD-L1 mouse model to assess renal effects of ICIs, alone or combined with proinflammatory cytokines, and to test if selective TNF-α blockade could prevent ICI-AIN. Mice were randomly divided into 4 experimental groups: Control, ICI-Only, ICI-Cytokines (ICI-Cyt), and ICI-Block (ICI-TNF-α blockade). Renal function and cytokine profiles were assessed, while kidney tissue was analyzed using microscopy and single-cell RNA-seq. Histology revealed increased renal infiltration of CD4 + /CD8 + T cells in ICI-treated groups and decreased TNF-α expression following TNF-α blockade. Additionally, kidney tissue ELISA demonstrated reduced IFN-γ levels following TNF-α blockade. Plasma IL-6, MCP-1, and TNF-α were lower in ICI-Block mice. Single-cell RNA-seq revealed shifts in immune cell populations and genes of interest including Bcl2a1 , Icos , Il18r1 , Ccr2 , and Jaml . This humanized model replicates ICI-AIN key features, revealing a synergistic role of ICIs and proinflammatory cytokines. TNF-α blockade demonstrated protective effects, supporting its potential role in mitigating the risk of ICI-AIN.

How is postural orthostatic tachycardia syndrome (POTS) diagnosed? What about adolescents who seem to have POTS but do not meet the diagnostic criteria? How can we treat POTS and related conditions? How can we best respond to common questions of frustrated patients and parents and guardians? This article provides evidence- and expert-based answers to questions that frequently arise when caring for patients with POTS and related conditions.

Summary Physical forces shape cell behavior, yet how they integrate with signaling to control fate and disease remains unclear. The alveolar epithelium is patterned by FGF signaling and mechanical stretch, but how these cues specify AT1 and AT2 cells is poorly understood. Here we show that cell membrane tension (CMT) is a conserved regulator of epithelial fate in mouse and human lungs. CMT drops before differentiation and is spatially patterned, defining where bipotent progenitors acquire AT1 or AT2 identity. Lower CMT enhances FGFR2 endocytosis and ERK signaling to drive AT2 differentiation and permits architectural remodeling that enables stretch-mediated YAP/TAZ nuclear entry for AT1 maturation. β-catenin elevates CMT cell-intrinsically independent of its role in canonical WNT transcription, while embedding, osmotic compression, or fibroblast wrapping elevate CMT extrinsically. Combined intrinsic and extrinsic tension traps alveolar epithelial cells in a KRT8⁺ transitional state seen in fibrotic lungs. Membrane tension thus integrates physical and molecular cues linking morphogenesis to fibrosis. Graphical Abstract In Brief We identify a conserved drop in cell membrane tension (CMT) that gates epithelial fate transitions across mouse and human lungs. In bipotent progenitors, reduced CMT promotes Alveolar Type 2 (AT2) fate via FGFR2 endocytosis and ERK signaling, as well as Alveolar Type 1 (AT1) fate by enabling architectural remodeling required for YAP/TAZ nuclear entry. We further show that intrinsic β-catenin and extrinsic confinement cues, including mesenchymal contact, converge to elevate CMT, restricting differentiation and—in adult AT2s—inducing a KRT8⁺ transitional state associated with fibrosis. Highlights Cell membrane tension drops before differentiation and is required for AT1 and AT2 fate acquisition. Reduced tension enhances FGFR2 endocytosis and ERK signaling to drive AT2 specification. Reduced tension permits architectural remodeling and YAP/TAZ nuclear entry required for AT1 maturation. Intrinsic β-catenin and extrinsic confinement elevate CMT to restrict differentiation and together strongly induce a KRT8⁺ transitional state associated with fibrosis.

Abstract Objective Advanced adrenocortical carcinoma (ACC) is treated with mitotane alone or combined with cytotoxic chemotherapy, yet outcomes remain poor and prognostic models in this setting are lacking. This study aimed to evaluate the prognostic value of clinical parameters in a large cohort of patients with advanced ACC undergoing systemic therapy. Methods Multicenter, international cohort study investigating 418 patients with advanced ACC (61.5% = women, median age = 52 years) from 11 centers. Patients received mitotane monotherapy (n = 161), etoposide + doxorubicin + cisplatin ± mitotane (n = 178), or second-line regimens (gemcitabine + capecitabine ± mitotane or temozolomide + mitotane, n = 79). Variables included age, cortisol excess, performance status (ECOG-PS), tumor burden, and neutrophil-to-lymphocyte ratio (NLR) at start of therapy. Outcomes were overall survival (OS), time to progression (TTP), and best objective response. Results Tumor burden, cortisol excess, ECOG-PS, and NLR ≥5 independently predicted shorter OS (hazard ratio [HR] 1.55-2.68). We developed an integrated ENSAT Risk Score for Advanced ACC combining these variables: tumor burden (0-2), cortisol excess (0/1), ECOG-PS (0-2), and NLR (0/1). A score >2 (poor-risk) was significantly associated with worse OS and TTP across all treatment groups (HRs for OS: 3.05-3.96; TTP: 2.53-3.08). It also predicted poorer response to mitotane (P < .01) and second-line therapies (P = .04). Conclusions The ENSAT Risk Score for Advanced ACC is a practical, prognostic tool for patients with advanced ACC receiving systemic therapy. Based on accessible clinical and biochemical markers, it can support treatment decisions and facilitate informed discussions in routine care.

Introduction: Zoledronic acid is a bisphosphonate widely used for osteoporosis and other bone disorders. In rare cases, it can cause ocular inflammation mimicking orbital cellulitis. Case description: A 52-year-old woman developed right eye pain and swelling within 24 hours of her first zoledronic acid infusion. Examination revealed conjunctival redness and mild eyelid swelling without proptosis, ophthalmoplegia, or vision loss. Laboratory markers were largely normal. Computed tomography scan and magnetic resonance imaging showed preseptal and postseptal inflammation without abscess formation. Treatment with corticosteroids and antibiotics resulted in complete symptom resolution within one week. Conclusion: Zoledronic acid can induce rapid-onset orbital inflammation. Awareness of this rare adverse effect is essential to avoid misdiagnosis and ensure timely treatment.