Citations

ABSTRACT Solid tissue‐derived extracellular vesicles (ST‐EVs) are extracellular vesicles (EVs) separated directly from solid tissues of both vertebrates and invertebrates. ST‐EVs provide a physiologically relevant snapshot of tissue‐specific molecular dynamics and can be enriched directly in situ, from tissues in their natural state, preserving the native characteristics of ST‐EVs. However, their enrichment presents unique technical challenges compared to EVs derived from biofluids or cell culture media. The need for transparent reporting in ST‐EV research is crucial to enhance the reproducibility, comparability, and reliability of research findings. The Solid Tissue Task Force, part of the Scientific Reproducibility Subcommittee of International Society for Extracellular Vesicles, aims to recommend reporting parameters and identify outstanding questions related to the pre‐analytical and analytical handling of solid tissues, as well as ST‐EV separation and characterization. These steps are essential for advancing the understanding of the biological roles of ST‐EVs and their potential clinical applications.

Abstract NF2-related schwannomatosis is a genetic condition characterized by mutation in the NF2 gene resulting in tumor formation throughout the nervous system. The most common tumors in these patients include bilateral vestibular schwannomas and multiple meningiomas which, despite their benign classification, lead to significant neurologic deficits including hearing loss, ataxia, hydrocephalus, and brainstem compression. Loss of NF2, which encodes the protein Merlin, is also the most common mutation in spontaneous meningiomas and schwannomas. Current treatment consists of resection followed by radiation for more aggressive tumors. Unfortunately, these treatments are not curative and are associated with significant risk due to tumor location, involvement of neurovasculature, cognitive impairment, and radiation-induced tumor induction. Therefore, identifying additional therapeutics for these patients is critical. Molecular profiling across large cohorts of sporadic meningiomas have identified molecular signatures associated with NF2 mutation, indicating upregulation of Wnt5a/b and the alternative Wnt5a/b-YAP/TAZ signaling pathway. In NF2 knock-out human arachnoid and Schwann cells, we find a significant upregulation of YAP in NF2-null lines compared to controls. Additionally, when stimulated with Wnt5a/b, controls upregulate both beta catenin (canonical Wnt) and YAP (alternative Wnt). However, in NF2-null lines only YAP is increased, indicating a preference for the alternative pathway in the absence of canonical Wnt signaling. In primary NF2-mutant meningioma lines, targeting this pathway via blocking Wnt secretion with the inhibitor LGK974 or YAP signaling with verteporfin, which is FDA approved, results in decreased cell viability and proliferation in vitro. These results indicate activation of the Wnt5a/b-YAP/TAZ alternative signaling pathway in NF2-mutant meningeal and Schwann cells, and a potential therapeutic effect of blocking this pathway in NF2-mutant meningiomas with a previously-FDA approved inhibitor. Additional research is needed on the receptors and molecular mediators playing a role in this pathway and how these drugs may have therapeutic benefits in vivo

Abstract High-grade gliomas represent the most common type of primary adult malignant brain tumor. IDH1/2 mutations are linked to lower-grade gliomas and better patient outcomes; however, molecular profiling has revealed additional alterations that drive aggression. CDKN2A/B loss in IDH-mutant astrocytoma is recognized as a key marker of grade 4 tumor biology, yet there remain no effective targeted therapies in aggressive gliomas. Here, we analyzed a cohort of patient-derived IDH-mutant astrocytoma with whole-exome and RNA sequencing data and identified several candidate genes and pathways concurrently regulated with CDKN2A/B loss, revealing an enhanced signature related to vascular processes. We sought to elucidate the angiogenic mechanisms and functional outcomes associated with high-grade behavior following CDKN2A/B loss in IDH-mutant astrocytoma to inform future therapeutic strategies. We used grade 4 IDH-mutant astrocytoma patient-derived xenograft (PDX) and established cell lines harboring homozygous CDKN2A/B deletion. We re-expressed the cell cycle regulators p14, p15, and p16 using a Tet-inducible lentiviral system and confirmed reduced proliferation compared to parental lines. Re-expression of p14, p15, or p16 also resulted in decreased glioma cell migration and invasion. Intriguingly, re-expressing these regulators reduced VEGF secretion. HUVEC cells cultured with conditioned media (CM) from the re-expression glioma lines decreased canonical activation of PI3K/Akt and Stat3 signaling and a diminished capacity to promote endothelial migration, invasion, and tube formation. Furthermore, in vivo Matrigel plug assays using CM from the re-expression lines showed a decreased ability to recruit endothelial cells, pericytes, and form vascular organized structures. We identified the WT1 transcription factor as an upstream regulator of angiogenesis. WT1 expression was inversely correlated with CDKN2A/B expression in patient data, and knockdown of WT1 in astrocytoma cells reduced VEGF secretion and impaired ability to promote endothelial migration. Taken together, our findings reveal a novel role for WT1 in VEGF-driven angiogenesis in IDH-mutant astrocytoma with CDKN2A/B homozygous deletion.

Objective To provide evidence‐based and expert guidance for the treatment and management of non‐renal systemic lupus erythematosus (SLE); treatment and management of lupus nephritis are addressed in a separate guideline. Methods Clinical questions for treatment and management of SLE were developed in the PICO format (population, intervention, comparator, and outcome). Systematic literature reviews were developed for each PICO question, and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was used to assess evidence quality and formulate recommendations. The Voting Panel achieved a consensus of ≥70% agreement on the direction (for or against) and strength (strong or conditional) of each recommendation. Results We present recommendations and ungraded, consensus‐based good practice statements for the treatment and management of SLE that are applicable to pediatric and adult patients. Recommendations emphasize uniform treatment with hydroxychloroquine, limiting duration of glucocorticoid use, and early introduction of conventional and/or biologic immunosuppressive therapies to achieve and maintain control of SLE inflammation (remission or a low level of disease activity), reduce SLE‐related morbidity and mortality, and minimize medication‐related toxicities. Conclusion This guideline presents direction regarding treatment and management of SLE and provides a foundation for well‐informed, shared clinician–patient decision‐making. These recommendations should not be used to limit or deny access to therapies, as treatment decisions may vary due to the unique clinical situation and personal preferences of each person with SLE.

Objective To provide evidence‐based and expert guidance for the treatment and management of non‐renal systemic lupus erythematosus (SLE); treatment and management of lupus nephritis are addressed in a separate guideline. Methods Clinical questions for treatment and management of SLE were developed in the PICO format (population, intervention, comparator, and outcome). Systematic literature reviews were developed for each PICO question, and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was used to assess evidence quality and formulate recommendations. The Voting Panel achieved a consensus of ≥70% agreement on the direction (for or against) and strength (strong or conditional) of each recommendation. Results We present recommendations and ungraded, consensus‐based good practice statements for the treatment and management of SLE that are applicable to pediatric and adult patients. Recommendations emphasize uniform treatment with hydroxychloroquine, limiting duration of glucocorticoid use, and early introduction of conventional and/or biologic immunosuppressive therapies to achieve and maintain control of SLE inflammation (remission or a low level of disease activity), reduce SLE‐related morbidity and mortality, and minimize medication‐related toxicities. Conclusion This guideline presents direction regarding treatment and management of SLE and provides a foundation for well‐informed, shared clinician–patient decision‐making. These recommendations should not be used to limit or deny access to therapies, as treatment decisions may vary due to the unique clinical situation and personal preferences of each person with SLE.

Objective A patient‐centered approach for chronic disease management, including systemic lupus erythematosus (SLE), aligns treatment with patients’ values and preferences, leading to improved outcomes. This paper summarizes how patient experiences, perspectives, and priorities informed the American College of Rheumatology (ACR) 2024 Lupus Nephritis (LN) and 2025 SLE screening, treatment guidelines. Methods We completed a cross‐sectional qualitative study using content analysis of two Patient Panel meetings for the ACR LN and SLE guidelines. Key themes were presented by Patient Panel representatives during Voting Panel Meetings along with evidence for each recommendation, to ensure comprehensive discussions and align treatment recommendations with patients’ priorities and values. Results Nineteen people (90% women) with diagnoses of SLE and/or LN participated in the Patient Panels and 17 consented to use their feedback for analysis. Thematic analysis of their discussions revealed nine patient‐reported key themes in three domains: (1) treatment and monitoring of LN and SLE: medication side effects, daily function, treatment goals, and monitoring and screening; (2) clinical communication: strategies to optimize communication and provider and structural impediments to effective communication; and (3) improving transparency and information sharing: clinical trial participation, and medical costs and insurance coverage. These themes were actively incorporated into discussions during the Voting Panels for the ACR LN and SLE guidelines. Conclusion This work supported the integration of patient experiences in the clinical practice guideline development process and aligned recommendations with real‐world patient experiences and priorities, thereby enhancing the clinical applicability of the ACR LN and SLE guidelines. image

Introduction: Corticosteroid therapy has been demonstrated to improve prognosis and reduce mortality in patients with severe Coronavirus Disease 2019 (COVID-19) infection by attenuating the exaggerated inflammatory response that emerges in the late phase of infection. However, its impact on patients with pre-existing cardiovascular disease, who are at higher risk of complications, has not been specifically studied. The aim of this study is to evaluate the effect of corticosteroid therapy on mortality and long-term COVID-19 symptoms in this high-risk population. Methods: We analyzed the prospective registry HOPE-2. Patients with previous cardiovascular disease were selected, and 18-month all-cause death was defined as the primary endpoint. Long-term COVID-19 symptoms were considered as secondary endpoints. A total of 1188 patients with previous heart disease were included, of which 453 received corticosteroid treatment. Propensity score matching analysis in a 1:1 fashion was performed based on baseline variables that exhibited a p-value < 0.05 in the univariant analysis and outcome variables that defined corticosteroid use, with a final matched population of 796 patients. Results: In patients with pre-existing heart disease, corticosteroid treatment was not associated with differences in 18-month all-cause mortality (p = 0.52). However, a shorter duration of hospitalization (median: 8 days [IQR: 4–14] and 11 days [IQR: 7–18]; p < 0.001) was observed in patients who received corticosteroids. No significant differences in long-term COVID-19 symptoms were observed between the two groups. Conclusions: In patients with pre-existing heart disease, the absence of a clear harmful effect suggests that the positive effects of corticosteroids may be offset by their potential adverse effects which could contribute to the persistence of long COVID symptoms. This finding may reflect a differential response to corticosteroids in this high-risk subgroup, highlighting the need for further studies to clarify the role of this therapy in such patients.

ABSTRACT The American Society for Apheresis (ASFA) Attending Physician Subcommittee of the Physicians' Committee performed an annual review of articles published in 2024 related to apheresis medicine. The 10 seminal apheresis articles selected by the subcommittee members are summarized in this review. PubMed was used to identify manuscripts published in 2024 in four areas of interest: donor apheresis, therapeutic apheresis, apheresis education, and apheresis for cellular therapy. Only full length, peer‐reviewed manuscripts in English with data from human subjects were included. Case reports, review articles, and meta‐analyses were excluded. Articles were considered seminal if they met at least one of the following previously established criteria: novel finding(s), practice‐altering outcomes, international in scope, randomized‐controlled trial, relevant to current clinical practice, and/or provide evidence for category III or IV indications based on the ASFA 9th special issue of the Guidelines on the Use of Therapeutic Apheresis in Clinical Practice‐Evidence‐Based Approach.