Citations

siRNA delivery to target cellular processes is an appealing area in lung diseases such as asthma. To realize this potential requires efficient, targeted cytosolic delivery without cellular toxicity or siRNA degradation. We demonstrate the efficacy of PONI-Guan nanoparticles in accessing airway epithelial and smooth muscle cells with specific siRNA targeting of mRNAs of interest while maintaining barrier integrity and avoiding cellular toxicity.

Abstract Background Peritumoral brain edema (PTBE) is a frequent complication of CNS tumors and radiation therapy (RT). PTBE is primarily treated with corticosteroids, but prolonged use is associated with severe toxicities including myopathy and immunosuppression. Bevacizumab, an alternative treatment, is not recommended in patients with thromboembolic events and intracerebral hemorrhage. Plasma kallikrein is a key driver of tumor-related edema. By targeting this pathogenic enzyme, the orally delivered inhibitor, RZ402, may provide therapeutic value by controlling edema and decreasing corticosteroid use. Methods In this single-patient investigational new drug protocol, we report results from use of RZ402 for treatment of cerebral edema related to metastatic melanoma and RT. Results A 74-year-old man with BRAF-wildtype melanoma had a right frontal and basal ganglia hemorrhagic metastasis not amenable to resection, treated with stereotactic RT (30 Gy, 5 fractions), followed by ipilimumab and nivolumab. MRI obtained 5 months after RT showed increased edema associated with midline shift. After 12 weeks of treatment with high-dose dexamethasone (16 mg daily), edema remained persistent and patient was unable to tolerate dose reduction below 4 mg daily. Course was complicated by a pulmonary embolus prompting initiation of anticoagulation, leading to deferral of bevacizumab. Patient was treated with RZ402, which was tolerated well with no reported toxicities. Dexamethasone was discontinued over 4 weeks. Follow up imaging 6 weeks after RZ402 initiation and off dexamethasone demonstrated stability without rebound edema. Patient did experience adrenal insufficiency characterized by severe fatigue, managed with low-dose prednisone. RZ402 was discontinued after 8 weeks of treatment with patient remaining clinically stable. Conclusion Despite persistent edema after prolonged use of corticosteroids, the selective plasma kallikrein inhibitor RZ402 was associated with radiographic stabilization and discontinuation of dexamethasone for this patient. These findings support prospective evaluation of RZ402 in treatment of symptomatic cerebral edema related to CNS tumors.

Importance Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis characterized by sterile ulcerative skin lesions. Multiple comorbidities and clinical features have been associated with PG, but no standardized guidelines exist for classifying PG phenotypes. Objective To develop an expert-established classification framework for PG phenotypes to inform treatment guidelines and future research endeavors. Evidence Review In this modified Delphi consensus study that included 23 board-certified dermatologists and Medical Dermatology Society members with expertise in PG, panelists completed 5 rounds of anonymous, iterative online surveys that were administered from December 2023 through July 2025. Before the beginning of the consensus exercise, a literature review was performed by nonvoting researchers to summarize existing data on PG clinical associations and comorbidities. A PubMed search from inception to September 2023 identified observational studies, narrative reviews, systematic reviews, and meta-analyses describing PG clinical associations and comorbidities that were published in English. Experts indicated their agreement with proposed PG phenotypes and disease modifiers with a consensus threshold of 70% or greater. Anonymous comments and aggregated results were presented in each subsequent round. In the final round, a framework of PG phenotypes and disease modifiers was proposed for agreement. Findings Twenty-three board-certified dermatologists and Medical Dermatology Society members with expertise in PG completed 5 rounds of iterative surveys. Consensus was reached on the final set of PG phenotypes and disease modifiers, with 83% of experts in agreement. PG phenotypes were overall classified into 2 major groups: PG with autoinflammatory syndromes and nonsyndromic PG. Nonsyndromic PG included 4 phenotypes: inflammatory bowel disease–associated PG, PG in association with hematologic cancers and blood dyscrasias, drug-induced PG, and other (including idiopathic) PG. Disease modifiers of PG phenotype presentations included involvement of special sites (head/neck, genitals, or peristomal skin) and extracutaneous manifestations. Conclusions and Relevance This expert-established, descriptive framework provides a standardized classification system for distinct PG phenotypes and its modifiers. This nomenclature may inform upcoming clinical guidelines and allow for consistency in reporting epidemiological research and outcomes among patients with PG.

Iron is an essential element for cellular homeostasis and functionality. Increased iron in the lung is associated with aging and asthma in the elderly (AIE). Using human airway smooth muscle cells from young versus elderly versus AIE patients, we found that dysregulated iron metabolism (more than iron accumulation), resulting in activation of antioxidant systems and increased susceptibility to ferroptosis, occurs in AIE, contributing to cell hyperplasia and matrix remodeling of aging and AIE.

Abstract Introduction Cutaneous lichen planus (cLP) is a T cell—mediated skin disease in which cytotoxic CD8+ T cells attack basal keratinocytes at the dermo-epidermal junction. While studies have characterized T cell subsets in lesional tissue, circulating immune signatures in cLP are incompletely defined. We performed deep immunophenotyping of circulating T-cell subsets to map systemic alterations in cLP patients vs healthy controls. Methods We included 12 treatment-refractory cLP patients (mean age 63.6 ± 13.6 years) and 2 healthy controls (37.5 ± 10.6 years). Whole blood was profiled for 27 markers by flow cytometry. Sequential gating: singlets → live → CD3+ T cells → CD4+/CD8+/γδ; FOXP3+ Tregs were defined within CD4+. Frequencies were expressed as % of the immediate parent population. Group comparisons used two-tailed exact Mann—Whitney tests with Hodges—Lehmann median differences. Results Across frozen specimens, cLP patients exhibited broad T-cell activation. Proliferation increased in CD4 (Ki67+, p < 0.05), CD8 (6.785% vs 0.885%; Δ=5.90; p < 0.05), and Tregs (83.0% vs 46.8%; Δ=34.1; p < 0.05). Intracellular CTLA-4 was higher on CD4 (11.07% vs 2.615%; Δ=8.45; p < 0.05), CD8 (21.05% vs 9.30%; Δ=11.6; p < 0.05), and γδ T cells (47.20% vs 24.45%; Δ=22.75; p < 0.05). CXCL13+ cells expanded in CD4 (28.20% vs 12.45%; Δ=15.5; p < 0.05), CD8 (18.05% vs 3.595%; Δ=14.46; p < 0.05), γδ (2.805% vs 0.465%; Δ=2.285; p < 0.05), and Tregs (7.56% vs 1.17%; Δ=6.39; p < 0.05). Tregs were TBET-high (78.75% vs 61.55%; Δ=17.3; p < 0.05); GITR+ Tregs trended up (p = 0.1978). Conclusion cLP blood displays a CXCL13+, proliferative T-cell signature with increased intracellular CTLA-4 across CD4, CD8, γδ, and Treg compartments. CXCL13 elevation aligns with lesion-level literature implicating CXCL13+ CD8+ T cells that are suppressed in JAK-STAT therapy responders. Tregs exhibit a GITR upregulated, Th1-like phenotype that suggests loss of suppressive capacity, warranting further investigation on whether Treg dysfunction plays a causative role in cLP. Funding Source N/A Topic Categories Immune Mechanisms of Human Disease (HUM)

Abstract Early-phase clinical trials of Bruton’s tyrosine kinase (BTK) degraders have demonstrated efficacy in patients with BTK inhibitor-resistant chronic lymphocytic leukemia (CLL). How clinical resistance to BTK degraders arises is unknown. Here we sequenced serial CLL samples from patients enrolled in the phase I trials of zelebrudomide and bexobrutideg and observed recurrent expansion of preexisting BTK A428D mutations at relapse. Unlike previously studied BTK inhibitor resistance mutations, BTK A428D conferred pan-resistance to BTK inhibitors and degraders. In the absence of BTK-directed therapies, however, cells bearing BTK A428D exhibited a competitive disadvantage. A crystal structure of BTK A428D revealed that the mutant aspartate clashes with the adenine ring of ATP and the adenine-mimetic moiety of BTK inhibitors and degraders. Combining BTK degraders with venetoclax mitigated the expansion of BTK A428D. These results provide the molecular basis for clinical resistance to BTK degraders and will inform the development of next-generation BTK degrader therapies.

Abstract INTRODUCTION Anti‐amyloid beta (Aβ) monoclonal antibodies are effective at lowering amyloid in Alzheimer's disease (AD). However, whether Fc‐mediated effector function is absolutely required for efficacy is not completely understood. This is important for optimizing therapeutic efficacy and mitigating side effects such as amyloid‐related imaging abnormalities (ARIA). Antibodies lacking Fc effector function, like single‐domain antibodies (nanobodies), offer a unique tool to dissect these mechanisms, as their small size facilitates blood–brain barrier (BBB) penetration and allows Fc‐mediated functions to be studied independently. METHODS We immunized a llama with Aβ aggregates and constructed a phage display library to screen for aggregate‐specific nanobodies. Lead candidates were characterized by epitope mapping and binding affinity to amyloid plaques in both murine and human AD brain tissues. We further assessed their BBB permeability and evaluated their efficacy in clearing pre‐existing plaques in amyloid precursor protein (APP)/presenilin 1 (PS1) mice. RESULTS We identified two lead nanobodies, 3A11 and 2D10, that bind distinct epitopes and specifically bind Aβ plaques in murine and human AD brain tissues. Following systemic administration, the monovalent, unmodified (Fc‐less) 2D10 nanobody, but not 3A11, successfully crossed the BBB and engaged amyloid plaques in APP/PS1 mice. However, despite robust target engagement, the Fc‐less 2D10 failed to recruit microglia or reduce plaque burden. In contrast, an engineered 2D10‐Fc fusion antibody potently cleared amyloid plaques, achieving a reduction in pathology comparable to aducanumab treatment. This efficacy was directly correlated with Fc‐mediated microglial recruitment and activation, demonstrating that the Fc domain is essential for phagocytic plaque removal. DISCUSSION Our findings demonstrate that Fc effector function is indispensable for microglial‐mediated amyloid clearance in vivo. By clarifying this fundamental mechanism, this study provides a framework for the rational design of next‐generation immunotherapies. Furthermore, 2D10‐Fc represents a promising therapeutic candidate, combining the high‐affinity targeting of nanobodies with the effector power necessary for robust plaque clearance.

Abstract Early-phase clinical trials of BTK degraders in relapsed/refractory CLL have shown response rates of over 80%, including in patients with BTK mutations that confer resistance to conventional BTK inhibitors (BTKi). The molecular basis of resistance to BTK degraders is unknown and, given the promise of this class of drugs, would hold implications for therapy sequencing and the design of next-generation BTK degraders. To this end we identified five patients at Memorial Sloan Kettering who developed progressive disease while being treated on the phase 1 trials of zelebrudomide (NCT04830137, 4 patients) or bexobrutideg (NCT05131022, 1 patient). In two patients, one treated with zelebrudomide and the other with bexobrutideg, a pre-existing BTK A428D mutation had expanded at progression, rising from <1.5% at the start of treatment to >25%. In both cases, the increase in frequency of BTK A428D coincided with the loss of BTK degradation in peripheral blood B cells. No mutation in cereblon, the ligase utilized by these BTK degraders, was detected. To validate these clinical findings we generated wild-type and BTK A428D knock-in single-cell clones in TMD8 and HBL1 cells. BTK A428D conferred resistance to BTKi, including ibrutinib, acalabrutinib, zanubrutinib, and pirtobrutinib, as well as the clinical-stage BTK degraders zelebrudomide, bexobrutideg, BGB-16673, and AbbVie-1 (Compound 1, WO 2023183811). BTK A428D’s pan-resistance is unique compared to previously studied BTKi resistance mutations which remain susceptible to at least one BTKi and all clinical-stage BTK degraders tested. To understand how BTK A428D confers pan-resistance to BTKi and BTK degraders we conducted surface plasmon resonance studies which demonstrated that BTKi and all four clinical-stage BTK degraders tested are unable to bind BTK A428D. We next solved the crystal structure of apo BTK A428D to 1.8Å, which revealed that the mutant aspartate, which is larger and negatively charged compared to the wild-type alanine, sterically blocks BTKi and degraders from accessing residues in the hinge region of the kinase that are required for drug binding. We next asked why BTK A428D, despite conferring pan-resistance, has only been detected in 1.1% of patients treated with BTK inhibitors. Intriguingly, we noted that in one of our index patients, the frequency of BTK A428D declined and became undetectable after the withdrawal of zelebrudomide, suggesting a fitness defect. To assess this hypothesis, we compared the proliferation rates of five TMD8 wild-type and five BTK A428D single-cell clones; the BTK A428D clones grew more slowly and were consistently outcompeted in mixing studies. In summary, low-frequency BTK A428D mutations can expand under the selection pressure of BTK degraders and confer clinical resistance by preventing drug binding. The mutation, however, is outcompeted in the absence of BTK-targeted therapies. These findings provide rationale for the investigation of combination therapies and the development of next-generation BTK degraders capable of circumventing BTK A428D. Citation Format: Quinlan Sievers, Hao Lu, Allison Cool, Stefan Grajewski, Tim Kong, Mark Noviski, Xiaoli Mi, Emel Ficici, Ratul Mukerji, James Iuliano, Jordan Ye, Mateo Sanchez Garcia de los Rios, Hugo Bousquet, Sarah Whelan, May Tan, Christopher Phelps, Jahan Raman, Ryan Notti, Lizbeth Mendoza Navarrete, Samantha Sekeres, Eria Lamkin, Eduardo Bravo, Mark Ewalt, Prioty Islam, Anthony Mato, Lindsey Roeker, Justin Taylor, Meghan Thompson, Gwenn Hansen, Omar Abdel-Wahab. BTK A428D is a recurrent pan-resistance mutation to BTK degraders in clinical trials [abstract]. In: Proceedings of the Fifth AACR International Meeting on Advances in Malignant Lymphoma: From Discovery to Clinical Impact; 2026 Jun 24-27; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2026;7(3_Suppl):Abstract nr PR004.

Abstract INTRODUCTION Women are increasingly entering the dementia research workforce, but they frequently fail to attain senior leadership positions in academia. Discrepancies in academic research outputs were investigated to guide equity‐focused policy recommendations. METHODS Bibliometrics was conducted on 400,482 original research articles (2003–2022) followed by surveying the AD/ADRD research community, to quantitatively and qualitatively evaluate discrepancies in publication and authorship trends. In addition, an unsupervised learning algorithm was developed to analyze underlying relationships between author groups. RESULTS Male author gender was consistently predictive of better publication and citation metrics across all bibliometrics outcomes, with senior male authors outperforming all other subgroups and fewer senior female authors in most research areas. Female survey respondents reported more barriers, but comparable productivity and citation strategies as male authors. DISCUSSION Multi‐pronged approaches by stakeholders across institutions, funders, and journals are necessary to provide career support for early‐career scientists working to transition to senior research roles.

The NCCN Guidelines for Melanoma: Cutaneous provide strategies for the diagnosis, treatment, and follow-up of patients with cutaneous melanoma, which is among the most common cancers in the United States. The outcome of cutaneous melanoma is significantly influenced by stage at initial presentation. Generally, localized disease and smaller primary tumors have been associated with more favorable prognosis. Thus, the select content featured in this issue focuses on risk factors associated with cutaneous melanoma development and which should be considered during an initial assessment. These include (1) phenotypic predispositions, (2) personal medical history or comorbidities, (3) genetic predispositions, and (4) environmental factors.