Vanessa Desantis

Background: Pompe disease is a rare, progressive lysosomal storage disorder caused by acid α-glucosidase deficiency, leading to glycogen accumulation, proximal muscle weakness, and respiratory decline. Enzyme replacement therapy (ERT) significantly improves survival and stabilizes motor function, but IgE-mediated hypersensitivity reactions (HSRs) can critically compromise treatment, posing a major clinical challenge. Desensitization protocols allow temporary tolerance to ERT, yet breakthrough reactions may occur, necessitating adjunctive strategies such as omalizumab. Results: We report a 40-year-old woman with late-onset Pompe disease who developed severe IgE-mediated HSRs to alglucosidase alfa after years of uneventful therapy. Basophil activation testing (BAT) and serum-specific IgE confirmed an IgE-mediated mechanism. A 15-step, 5-bag desensitization protocol allowed temporary tolerance, but breakthrough reactions required therapy interruption. Upon switching to avalglucosidase alfa, BAT demonstrated IgE cross-reactivity, and a new desensitization protocol was implemented. Initial infusions were complicated by recurrent HSRs. The addition of subcutaneous omalizumab (300 mg monthly), administered two days before ERT, enabled safe reintroduction. Moreover, therapy was resumed gradually, starting at 50% of the target dose and escalating stepwise to the full therapeutic dose, resulting in uninterrupted treatment. Follow-up showed stable neuromuscular and respiratory function, progressive decline in BAT reactivity, and improved quality of life. Conclusions: This case highlights the critical role of BAT in diagnosing and monitoring IgE-mediated HSRs, the efficacy of individualized desensitization protocols, and the utility of omalizumab as an adjunctive therapy in refractory cases. In rare diseases like Pompe, documenting such integrated allergological strategies provides practical guidance for maintaining access to life-prolonging therapy and offers a reproducible framework for managing complex allergic complications.

ADAM17 (a disintegrin and metalloproteinase 17) is increasingly recognized as a central regulator of multiple myeloma (MM) biology beyond its canonical role in TNF-α shedding. Rather than acting as a classical oncogenic driver, ADAM17 functions as a master regulator of ectodomain shedding, controlling the balance between membrane-bound and soluble mediators that shape signaling across the bone marrow microenvironment. Through coordinated processing of cytokines, cytokine receptors, growth factor ligands, and adhesion molecules, ADAM17 amplifies inflammatory signaling, endothelial activation, immune dysfunction, and tumor dissemination.In MM, ADAM17 contributes to key pathogenic processes by modulating the spatial and temporal dynamics of extracellular communication. Shedding of CX3CL1 and adhesion molecules such as JAM-A promotes angiogenesis and vascular niche remodeling, while IL-6R cleavage enables trans-signaling that sustains stromal activation, chronic inflammation, and malignant plasma cell survival. In parallel, ADAM17-dependent processing of immune receptors, including CD62L, alters lymphocyte trafficking and immune surveillance, contributing to an immunologically permissive niche. Proteolytic remodeling of adhesion systems may also facilitate niche escape and extramedullary dissemination.These coordinated shedding events define a dynamic myeloma “sheddome,” in which ADAM17 acts as a systems-level node integrating tumor, stromal, endothelial, and immune signals. This framework helps explain the context-dependent and pleiotropic effects of ADAM17 throughout disease evolution. Clinically, circulating ADAM17 shows promise as a dynamic biomarker reflecting tumor burden, microenvironmental activation, and immune dysfunction. However, therapeutic targeting remains challenging because of substrate redundancy, systemic functions, and the risk of disrupting physiological immune regulation. Future strategies will require selective and context-aware modulation of ADAM17-driven shedding networks to effectively reprogram the myeloma microenvironment.

Heart failure (HF) is closely linked to endothelial dysfunction, which contributes significantly to its progression. Endothelial dysfunction in HF is marked by reduced nitric oxide bioavailability, increased oxidative stress and inflammation, all of which impair vascular function. Endothelial progenitor cells (EPCs) – vital for vascular repair – are particularly affected, with their dysfunction further exacerbating HF outcomes. Emerging therapies targeting these mechanisms, including antioxidants, gene therapies enhancing endothelial nitric oxide synthase activity and EPC-based strategies, hold promise. Recent advances show encouraging results, especially with treatments improving EPC mobilisation and function. Additionally, pharmacological agents such as statins and sodium–glucose cotransporter 2 inhibitors demonstrate pleiotropic benefits, enhancing endothelial health and EPC activity. This review emphasises the therapeutic potential of these approaches, highlighting the critical need for further research to optimise endothelial-targeted treatments and improve outcomes for HF patients.

Multiple myeloma (MM) is driven by clonal plasma cell (cPC)–intrinsic factors and changes in the tumor microenvironment (TME). To investigate whether residual polyclonal PCs (pPCs) are disrupted, single-cell (sc) RNA sequencing (scRNA-seq) and sc B-cell receptor analysis were applied in a cohort of 46 samples with PC dyscrasias and 21 healthy donors (HDs). Of 234 789 PCs, 64 432 were genotypically identified as pPCs with frequencies decreasing over different disease stages, from 23.66% in monoclonal gammopathy of undetermined significance to 3.23% in MMs (P = .00012). Both cPCs and pPCs had a comparable expression of typical lineage markers (ie, CD38 and CD138), whereas others were more variable (CD27 and ITGB7). Only cPCs overexpressed oncogenes (eg, CCND1/2 and NSD2), but CCND3 was often expressed in pPCs. B-cell maturation antigen was expressed on both pPCs and cPCs, whereas GPRC5D was mostly upregulated in cPCs with implications for on-target, off-tumor activity of targeted immunotherapies. In comparison with HDs, pPCs from patients showed upregulated autophagy and disrupted interaction with TME. Importantly, interferon-related pathways were significantly enriched in pPCs from patients vs HDs (adjusted P < .05) showing an inflamed phenotype affecting genotypically normal PCs. The function of pPCs was consequently affected and correlated with immunoparesis, driven by disrupted cellular interactions with TME. Leveraging our scRNA-seq data, we derived a “healthy PC signature” that could be applied to bulk transcriptomics from the CoMMpass data set and predicted significantly better progression-free survival and overall survival (log-rank P < .05 for both). Our findings show that genotypic sc identification of pPCs in PC dyscrasias has relevant pathogenic and clinical implications.

Dupilumab, a monoclonal antibody targeting the interleukin (IL)-4 receptor alpha subunit and IL-13, has markedly advanced the treatment of atopic conditions such as dermatitis, asthma, and chronic rhinosinusitis. However, its expanding use has brought increased attention to a range of ocular adverse events—conjunctivitis, blepharitis, keratitis, corneal ulcers, and cicatricial conjunctivitis—that remain underrecognized and frequently underestimated in clinical practice. These manifestations often emerge in patients with atopic dermatitis and display varying severity, posing diagnostic and therapeutic challenges. Rather than isolated phenomena, these effects appear to stem from a complex interplay of goblet cell depletion, mucin deficiency, immune dysregulation, and microbiome alterations, including Demodex proliferation. Current management strategies remain largely empirical, lacking standardized protocols, and are often guided by anecdotal evidence. In this review, we critically appraise the existing literature, synthesize emerging pathogenic hypotheses, and highlight the unmet clinical need for evidence-based treatment algorithms. We advocate for a multidisciplinary approach and future research aimed at elucidating mechanisms, refining risk stratification, and minimizing ocular toxicity without compromising the therapeutic benefits of dupilumab. Furthermore, we intend to provide a more practical and straightforward resource for the reader based on the current literature on approaching the topic.

At its earliest appearance, atrial fibrillation (AF) is often unnoticed, asymptomatic, and/or merely device-detected. Widespread use of heart-rate monitoring technologies has facilitated such “nascent atrial fibrillation (nAF)” recognition. Consequently, clinicians face a growing number of patients affected by new-onset AF in the absence of a definite indication for anticoagulation due to several counterarguments: (1) a CHA₂DS₂-VA score ≤ 1 in otherwise apparently healthy subjects; (2) an uncertain embolic/hemorrhagic benefit/risk ratio with anticoagulation; (3) EKG demonstration and confirmation of AF; and (4) existence of a pathogenic mechanism other than atrial hypercoagulability. In this frustrating limitation of pharmacological options, cardiologists may miss a complete comprehension of drugs with proven anti-ictal potential, whose administration may serve both as a bridge strategy toward future anticoagulation and as a consolidative strategy paralleling anticoagulation. This review aims to summarize and elucidate such therapeutic strategies and their preventative mechanisms.

Here we show that under oxygen-glucose deprivation (OGD), multiple myeloma cells transfer dysfunctional mitochondria to bone marrow stromal cells (BMSCs) for degradation (transmitophagy). These mitochondria are then transferred between BMSCs via tunneling nanotubes contributing to myeloma survival in OGD.

Pancreatic ductal adenocarcinoma (PDAC) presents significant oncological challenges due to its aggressive nature and poor prognosis. The tumor microenvironment (TME) plays a critical role in progression and treatment resistance. Non-neoplastic cells, such as cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs), contribute to tumor growth, angiogenesis, and immune evasion. Although immune cells infiltrate TME, tumor cells evade immune responses by secreting chemokines and expressing immune checkpoint inhibitors (ICIs). Vascular components, like endothelial cells and pericytes, stimulate angiogenesis to support tumor growth, while adipocytes secrete factors that promote cell growth, invasion, and treatment resistance. Additionally, perineural invasion, a characteristic feature of PDAC, contributes to local recurrence and poor prognosis. Moreover, key signaling pathways including Kirsten rat sarcoma viral oncogene (KRAS), transforming growth factor beta (TGF-β), Notch, hypoxia-inducible factor (HIF), and Wnt/β-catenin drive tumor progression and resistance. Targeting the TME is crucial for developing effective therapies, including strategies like inhibiting CAFs, modulating immune response, disrupting angiogenesis, and blocking neural cell interactions. A recent multi-omic approach has identified signature genes associated with anoikis resistance, which could serve as prognostic biomarkers and targets for personalized therapy.