Citations

ABSTRACT Extracellular vesicles (EVs) are membrane‐enclosed nanoparticles that mediate intercellular communication by transferring proteins, nucleic acids, and lipids. Within the hematopoietic system, EVs orchestrate critical signaling between bone marrow (BM) niche cells and hematopoietic stem and progenitor cells (HSPCs) to regulate quiescence, proliferation, and lineage commitment. During aging, senescence and telomere attrition drive a profound remodeling of EV biogenesis and cargo. Aged EVs, particularly those released from senescent mesenchymal stromal cells (MSCs) and osteoblasts, exhibit altered microRNA profiles and reduced protective antioxidants. These changes perpetuate niche dysfunction, induce senescence in recipient cells, and promote myeloid‐biased hematopoiesis. Importantly, this communication is a selective process governed by vesicle‐intrinsic surface signatures, such as tetraspanins and integrins, which interact with specific receptors on distinct hematopoietic subsets to regulate signaling fidelity. Conversely, EVs from young or pluripotent stem cells deliver rejuvenating signals that can restore aged HSPC function and attenuate inflammaging. Elucidating these mechanisms of selective targeting and stress‐responsive cargo remodeling provides vital insights for developing EV‐based diagnostic tools and rejuvenation strategies to prevent age‐related immune imbalances and hematologic malignancies.

Advanced-stage high grade serous ovarian cancer (HGSC) initially responds to platinum-based chemotherapy; however, most HGSC tumors recur and develop chemotherapy-resistance, making recurrent ovarian cancer (OC) a fatal disease. Ovarian cancer stem cells (OCSCs), a subpopulation of cells capable of surviving treatment and repopulating tumors, contribute to disease relapse, and understanding the mechanisms(s) responsible for OCSC survival is critical for developing strategies to overcome acquired resistance and prevent tumor recurrence. However, whether platinum-induced OCSC enrichment results from the selection of pre-existing OCSCs or chemotherapy-induced cellular plasticity, and the molecular mechanisms underlying these processes, remain poorly understood. Here, we demonstrated that cisplatin treatment not only enriched for OCSCs but promoted the conversion of ALDH- cells to ALDH+ cells, revealing chemotherapy-induced plasticity as a potential mechanism for OCSC expansion. This conversion was associated with nuclear receptor signaling pathways, vitamin D receptor signaling (VDR/RXR) and retinoic acid receptor signaling (RAR/RXR). Importantly, activation of VDR/RXR signaling with vitamin D reduced stemness phenotypes and the cisplatin induced conversion to ALDH+ cells. In addition, vitamin D combined with cisplatin decreased tumor volume in vivo compared to either treatment alone. In contrast, cisplatin treatment increased RAR/RXR signaling, supporting an associative role for ligand-dependent nuclear receptor signaling in OCSC plasticity. Together, these findings reveal that platinum chemotherapy can actively promote the acquisition of stem-like properties and identifies VDR/RXR signaling as a potential regulatory mechanism of OCSC plasticity. Targeting this pathway with vitamin D may provide a therapeutic strategy to target OCSCs and improve responses to platinum-based chemotherapy.

Abstract Post-traumatic headache (PTH) is the most common consequence of mild traumatic brain injury (mTBI) and often resembles migraine. In 20% to 30% of migraine patients, headaches are preceded by aura, transient visual or sensory disturbances, which are caused by cortical spreading depression (CSD) that can induce headache pain. However, whether mTBI promotes the development of aura and CSD and their possible contributions to PTH remains unclear. We examined the incidence of new-onset aura in individuals with PTH who had no history of aura. Thirty-two percent (35/108) developed new aura symptoms within 60 days of injury, suggesting that mTBI can sensitize the cortex to the induction of CSD. To test this, we combined electrophysiology, neuroimaging, and behavioral assays in a mouse model of mTBI-induced PTH. After closed-head mTBI, injured mice exhibited a 160% increase in CSD induction probability (ie, lowered threshold) and became sensitized to CSD induction by brief exposure to stress, a common headache trigger. When evoked optogenetically, CSD produced prolonged periorbital and hind paw allodynia, consistent with headache-like pain. Subcutaneous onabotulinumtoxinA administered to the scalp after mTBI did not alter CSD susceptibility but completely abolished optogenetic CSD-induced allodynia. These findings suggest that mTBI elicits sensitization to CSD induction and promotes the emergence of aura in humans, likely contributing to PTH. It is important that, even after mTBI-induced sensitization, onabotulinumtoxinA decoupled CSD from pain behaviors, suggesting efficacy in treating PTH associated with aura.

Abstract Recent evidence implicates somatic mutations in disease-associated genes across multiple neurodegenerative disorders, including the identification of two somatic TARDBP variants as a putative cause of frontotemporal lobar degeneration with TDP-43 pathology type C (FTLD-TDP type C). However, these findings remain anecdotal. We performed single-nucleus amplicon sequencing of 39,800 neurons from the superior temporal gyrus of sporadic FTLD-TDP type C patients (34,738 neurons, 52 individuals) and non-demented controls (5,062 neurons, 26 individuals) using the Mission Bio Tapestri platform and investigated somatic variants in TARDBP and other FTLD-TDP-associated genes in a case-control setting. We uncovered an extensive landscape of ultra-low-frequency (<1%) somatic mutations across all analysed genes, including TARDBP . Rare somatic occurrences of known ALS/FTD-associated germline TARDBP variants, including p.N267S and p.M337V, were identified exclusively in patients. Among all targeted genes, TARDBP had the highest proportion of neurons harbouring a somatic variant, and this mutational burden was lower in individuals who died at an older age. Strikingly, the C-terminal domain of TDP-43, where most ALS/FTD germline pathogenic variants reside, exhibited a lower neuronal mutational burden than its other domains. This suggests that neurons harbouring damaging mutations may undergo progressive loss prior to autopsy, leaving only rare survivors at frequencies too low to detect by bulk or small-scale single-cell approaches. Together, our findings provide an unprecedented resolution into the somatic mutational landscape of post-mitotic neurons in FTLD-TDP type C and reveal a gene-specific layer of neuronal mosaicism that current single-cell WGS studies fail to detect.

Background/Objectives: Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome and hemophagocytic lymphohistiocytosis (HLH) are life-threatening conditions characterized by immune dysregulation. Several reports have identified an overlap between these entities; however, clinical characteristics, triggers, and outcomes remain poorly defined. The objective of this study was to characterize the clinical features and outcomes of DRESS/HLH overlap syndrome. Methods: We conducted a PRISMA-guided systematic review of PubMed, Embase, and MEDLINE. Studies were included if they reported cases meeting criteria for DRESS syndrome and HLH. Results: Thirty-six patients were included, 75% female and 27.8% pediatric. Initial misdiagnosis occurred in 30.6% and was associated with higher mortality (45.5% vs. 20.0%). Antibiotics were the most frequent triggers (36.1%) and 11.1% of patients had no trigger identified. Mean latency was 27.9 days for DRESS syndrome and 35 days for HLH, with shorter latency in antibiotic-associated cases. DRESS syndrome and HLH most commonly occurred sequentially (n = 22, 61.1%) and in 52.8% of cases DRESS preceded HLH. Fever and rash were present in 88.9%. Laboratory abnormalities included hyperferritinemia (91.7%), eosinophilia (77.8%), anemia (75.0%), and thrombocytopenia (75.0%). Hepatic involvement was nearly universal (94.4%), followed by renal involvement (36.1%). Viral reactivation was observed in 38.9%, multiorgan failure in 36.1%, and ICU admission in 19.4% of cases. Mortality was 27.8% and higher in steroid-refractory cases and those with multiorgan failure. Treatment included corticosteroids (97.2%), with IVIG (33.3%), etoposide (13.9%), and cyclosporine (5.6%) used in severe cases. Conclusions: DRESS-HLH overlap represents a severe hyperinflammatory syndrome with high mortality. Early recognition and escalation of therapy are essential to improve outcomes. This is the largest and most uniformly characterized cohort of DRESS/HLH overlap reported to date, and the first to stratify mortality by diagnostic accuracy, temporal pattern, corticosteroid responsiveness, and multiorgan failure. Because the syndrome is rare and the evidence base consists almost entirely of single-case reports, multicenter collaboration and a prospective registry are needed to define incidence and optimal therapy.

Importance Lichen planus is a chronic, highly pruritic, inflammatory disease that affects the skin and other tissues. Objective To evaluate the efficacy and safety of ruxolitinib, 1.5%, cream in patients with cutaneous lichen planus. Design, Setting, and Participants This phase 2, 16-week, randomized, double-blind, vehicle-controlled trial with a 16-week open-label extension was conducted from November 2022 to February 2024. Patients were enrolled from 19 sites in the US and Canada. The trial included adults with predominantly cutaneous lichen planus, an Investigator’s Global Assessment (IGA) score of 3 or 4, an Itch Numerical Rating Scale score of 4 or greater, and an affected body surface area of 20% or less were enrolled. Data were analyzed from February to August 2024. Interventions Patients were randomized 1:1 to ruxolitinib, 1.5%, twice daily cream or vehicle cream for 16 weeks, after which eligible patients applied ruxolitinib cream twice daily as needed in a 16-week, open-label extension. Main Outcomes and Measures The primary end point was IGA treatment success (IGA score of 0 or 1 [clear/almost clear skin] with a ≥2-grade improvement from baseline) at week 16. Results Among 64 randomized patients, 46 (72%) were female, 18 (28%) were male, 18 (28%) were African American/Black, 4 (6%) were Asian, 40 (63%) were White, and the median (range) age was 57.0 (18-78) years. Significantly more patients who applied ruxolitinib, 1.5%, cream vs vehicle achieved IGA treatment success (50.0% [95% CI, 31.9%-68.1%] vs 21.9% [95% CI, 9.3%-40.0%], respectively; response rate difference, 29.4% [95% CI, 7.6%-51.3%]; P = .01; primary end point) at week 16, with further improvement to week 32. Similar results were observed in the proportion of patients who achieved a 4 or greater–point improvement from baseline in Itch Numerical Rating Scale score (week 16, 48.4% [95% CI, 30.2%-66.9%] vs 16.1% [95% CI, 5.5%-33.7%]; response rate difference, 33.5%; 95% CI, 12.2%-54.9%; P = .004; secondary end point). No serious treatment-emergent adverse events or discontinuations due to an adverse event were observed with ruxolitinib cream. Conclusions and Relevance The results of this randomized clinical trial suggest that ruxolitinib cream significantly reduced lesions and itch in patients with lichen planus. Therefore, ruxolitinib cream represents a potential treatment option for patients with cutaneous lichen planus. Trial Registration ClinicalTrials.gov Identifier: NCT05593432

BACKGROUND: Hemorrhoids are common and relief anchors on symptom improvement. Despite several available treatment options, the optimal patient-reported outcome measure for contemporary clinical trials is not established. OBJECTIVE: We aimed to systematically assess patient-reported outcome measures that measure hemorrhoid symptom severity and/or health-related quality of life. DATA SOURCES: A systematic review was performed using PubMed and Embase (1980-2025). STUDY SELECTION: Prospective development/validation studies evaluating patient-reported outcome measures relevant to hemorrhoidal disease. MAIN OUTCOME MEASURES: Patient-reported outcome measures were evaluated on key measurement properties of reliability, internal consistency, construct validity, and responsiveness according to COSMIN v2.0 criteria. RESULTS: Of the 1,266 total studies reviewed, nine patient-reported outcome measures were identified: seven measure symptom severity and six measure health-related quality-of-life. Three demonstrated reliability, internal consistency, construct validity, and responsiveness. The Patient Reported Outcome Measure-Haemorrhoidal Impact And Satisfaction Score comprehensively measures symptom severity, health-related quality-of-life, and treatment satisfaction. The Hemorrhoidal Disease Symptom Score classifies patients with high or low symptom load, and when used in combination with Short Health Scale-Hemorrhoidal Disease, also measures impact on health-related quality of life. LIMITATIONS: Preference toward specific measures may differ between clinical trials and clinical practice. CONCLUSIONS: We identify two viable patient-reported outcome measures for use in future clinical trials that evaluate hemorrhoid interventions.