Delayed grip relaxation is a common symptom of myotonic dystrophy type 1 (DM1), differing from other muscle diseases. Preclinical studies suggest myotonia may reverse quickly with targeted treatment and video hand opening time (vHOT) could be a straightforward method for assessing myotonia in multicenter trials, but few studies have evaluated vHOT in large DM1 cohorts. This study aimed to evaluate how vHOT performs and relates to other disease aspects in a large, well-characterized DM1 population. The vHOT was conducted in the END-DM1 natural history study across 22 international sites, including adult DM1 patients with a genetic or research criteria diagnosis. The primary outcome involved video-recorded hand opening after a maximum 3-second grip, performed twice at each study visit with 5-minute rest between trials, and blinded scoring at a central site. Muscle strength and function were assessed by myometry, timed functional tests, and patient-reported outcomes. Procedures were repeated after 1 year for a subset of participants. Wilcoxon signed-rank was used to evaluate differences and Spearman correlation for associations. A total of 591 patients with DM1 (mean age 43.7 ± 12.9 years, 57% female) were included, showing a broad spectrum of vHOT severity (median 3.9 seconds, interquartile range 1.8-7.9 seconds). At a single study visit, there were no systematic difference and good agreement between trials (mean difference 0.1 ± 3.7 seconds [p = 0.05], intraclass correlation coefficient 0.84 [95% CI 0.81-0.86]). vHOT correlated relatively weak with self-reported myotonia (ρ = 0.39), and even lower for other measures of muscle impairments such as grip strength (ρ = -0.21) or 9-hole pegboard (ρ = 0.12). 270 patients completed the 1-year follow-up, with vHOT showing no progression (mean difference 0.4 ± 4.7 seconds, p = 0.34). The vHOT procedure was performed successfully in a large international study, with grip relaxation delay varying from minimal to highly prolonged in an unselected cohort. The weak correlation with grip weakness supports the notion that myotonia and weakness are mechanistically distinct. Study limitations include underrepresentation of congenital DM1 and lack of other myotonia measures (e.g., handgrip relaxation myometry). It seems that vHOT is not suitable to assess disease progression, but stability over 1 year may support its use to assess improvement. The END-DM1 observational study is registered with number NCT03981575.

Multi-level dynamic fusion and temporal role-aware network for diagnosis prediction.

Determinants of morbidity and local control after cryoablation of sporadic extra-abdominal desmoid tumors.

A growing population of people living with Alzheimer's Disease requires improved supports for aging in place. Assistive technologies (ATs) can delay institutionalization, reduce care partner strain, and improve quality of life for this population. The abilities and needs of this population change during disease progression, but it remains unclear which ATs are best suited for specific stages. The purpose of this scoping review was to provide a snapshot in time by mapping currently available ATs assessed in peer-reviewed research, across the seven stages of Alzheimer's Disease progression. The review followed the Arksey and O'Malley framework to identify and harvest information from Medline, Scopus, CINAHL, and Embase databases. Inclusion criteria were Alzheimer's Disease, technology interventions of any type and duration, English language, and the period between 2000 and 2023. Data was extracted and analyzed using six predetermined domains of ATs for dementia: safety devices, clinical devices, memory aids, ATs for preventing social isolation, ATs for leisure activities, and ATs for supporting everyday tasks. A total of 87 ATs, reported in 47 articles, were mapped along seven stages of the disease. A variety of ATs are available, with high technology (e.g., tracking devices) targeting initial stages, and low technology (e.g., weighted blanket) targeting later stages. Music therapies were present across all disease stages. The map has the potential to inform people with Alzheimer's Disease, care partners, technology companies, policy makers and service providers on current AT availability and need for further development.

Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by steatosis, inflammation, hepatocellular injury and fibrosis, with the capacity to progress to cirrhosis and hepatocellular carcinoma. Recent evidence highlights cellular senescence, particularly in hepatic stellate cells (HSCs) as a key regulator of MASH pathogenesis. Senescent HSCs exhibit a context-dependent duality whereby, while transient senescence limits fibrosis through cell-cycle arrest, matrix degradation and enhanced immune clearance, persistent senescence under chronic metabolic and inflammatory stress drives disease progression. Through an expanded senescence-associated secretory phenotype (SASP), senescent HSCs exacerbate inflammation, promote extracellular matrix deposition, alter immune responses and facilitate malignant transformation. The present review summarizes the molecular mechanisms inducing HSC senescence, including lipotoxicity, oxidative stress, DNA damage, mitochondrial dysfunction and impaired autophagy. The mechanisms by which SASP factors mediate crosstalk between senescent HSCs and other cell types are discussed, including hepatocytes, macrophages, T cells and natural killer cells, collectively altering the inflammatory and fibrotic microenvironment of MASH. Finally, emerging therapeutic strategies targeting cellular senescence are highlighted, such as senolytics, senomorphics and biomarker-guided interventions, which may offer promising avenues for modifying the course of MASH and preventing disease progression.

Autophagy and cellular senescence are fundamental stress-response programs that critically shape aging and disease progression, yet their functional relationship has remained paradoxical. Autophagy is traditionally viewed as a cytoprotective process that preserves cellular homeostasis and delays senescence. In contrast, emerging evidence demonstrates that autophagy is also indispensable for the survival and pathological activity of established senescent cells. In this review, we propose a "threshold model" to reconcile these opposing roles and to provide a unified framework linking signal transduction, organelle quality control, and therapeutic intervention. According to this model, autophagy exerts stage-dependent functions governed by stress intensity and disease progression. Below a critical damage threshold, robust autophagic flux suppresses senescence initiation by maintaining mitochondrial integrity, limiting oxidative stress, and preserving proteostasis. Once this threshold is exceeded, autophagy is functionally reprogrammed to sustain the metabolic and biosynthetic demands of senescent cells, including production of the senescence-associated secretory phenotype (SASP). We highlight key signaling nodes that regulate this transition, including mTORC1, AMPK, p53, and p62, as well as spatial and organelle-specific mechanisms such as the TOR-autophagy spatial coupling compartment (TASCC), mitophagy failure, lipophagy blockade, and aberrant nucleophagy. These processes converge on innate immune pathways, notably cGAS-STING and NF-κB signaling, to drive chronic inflammation and tissue dysfunction. Importantly, we extend this mechanistic framework to clinical translation, synthesizing evidence from ongoing trials in cancer, neurodegeneration, metabolic liver disease, and fibrosis. We argue that effective targeting of the autophagy-senescence axis requires precision gerontology, integrating dynamic biomarkers to guide stage-specific interventions-autophagy activation for prevention and autophagy inhibition or senolysis for established disease. This threshold-based perspective provides a rational foundation for next-generation therapeutic strategies targeting aging and age-related disorders.

This preliminary study aimed to evaluate the safety and efficacy of 225Ac-DOTA-IBA in the treatment of bone metastases. Fourteen patients with bone metastases were enrolled and received at least one cycle of 225Ac-DOTA-IBA at a fixed dose of 3.7 MBq per cycle. Treatment-related adverse events (AEs) were graded according to the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0). Efficacy assessments included Eastern Cooperative Oncology Group (ECOG) performance status, Karnofsky Performance Status (KPS), and pain Numeric Rating Scale (NRS) scores at baseline and 2-4 weeks post-treatment, as well as 68Ga-DOTA-IBA PET/CT scans within 1 week before treatment and 4-8 weeks post-treatment. Imaging responses were categorized as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). 225Ac-DOTA-IBA was well tolerated, with no grade 3/4 AEs. On the basis of NRS scores, the pain relief rate was 92.9% (13/14) after the first cycle and was maintained at this level after subsequent cycles. ECOG performance status remained stable in the majority of patients, with improvement (from grade 2 to 1) observed in 2 cases (14.3%). KPS improved in 71.4% (10/14) of all patients after treatment. 68Ga-DOTA-IBA PET/CT analysis showed PR in 50.0% (7/14), SD in 35.7% (5/14), and PD in 14.2% (2/14). Among 7 patients who had previously received 177Lu-DOTA-IBA, 57.1% (4/7) improved in KPS, and 85.7% (6/7) in NRS. Regarding imaging response in these 7 patients, 42.9% (3/7) achieved PR, 42.9% (3/7) had SD, and 14.3% (1/7) showed PD. Subgroup analysis revealed that patients with bone-only metastases (n=9) had a significantly higher rate of KPS improvement (77.8% vs. 60.0%, P=0.012) and achieved a greater median reduction in pain scores (3.0 vs. 2.0 points, P=0.008). This study indicated that 225Ac-DOTA-IBA was a promising and well-tolerated therapeutic for bone metastases, demonstrating acceptable toxicity and notable efficacy, including 177Lu-DOTA-IBA-refractory cases. Subgroup analyses indicated that patients with bone-only metastases derived particular clinical benefit.

Metabolic reprogramming in lacrimal gland GVHD: Stage-specific shifts in acinar cells as drivers of disease progression.

Vascular smooth muscle cells (VSMCs) are the primary contractile component of blood vessels and can undergo phenotypic switching from a contractile to a synthetic phenotype in vascular diseases such as coronary artery disease (CAD) and restenosis. This process leads to decreased expression of SMC lineage genes and increased proliferative, migratory and secretory abilities that drive disease progression. Super-enhancers (SE) and lineage-specific transcription factors are believed to drive expression of genes that maintain cell identity and homeostasis. The goal of this study is to identify novel regulators of VSMC homeostasis by screening for SE-regulated transcription factors in arterial tissues. We characterized human artery SEs by analyzing the enhancer histone mark H3K27ac ChIP-seq data of multiple arterial tissues. We unexpectedly discovered the transcription factor PRDM16, a GWAS-identified CAD risk gene with previously well-documented roles in brown adipocytes but with an unknown function in vascular disease progression, is enriched with artery-specific SEs. Further analysis of public bulk RNA-seq and scRNA-seq datasets, as well as qRT-PCR and Western blotting analysis, demonstrated that PRDM16 is highly expressed in arterial tissues and in contractile VSMCs but not in visceral SMCs, and down-regulated in phenotypically modulated VSMCs. To explore the function of Prdm16 in vivo, we generated both inducible and constitutive Prdm16 SMC-specific knockout mice and performed bulk RNA-Seq analysis of aortic tissues and left carotid artery ligation to assess neointima formation. SMC-deficiency of Prdm16 does not affect the aortic morphology at baseline but significantly alters expression of many genes involved in VSMC homeostasis and cardiovascular disease, and suppresses VSMC proliferation and neointima formation in male mice. Specifically, Prdm16 negatively regulates the expression of Tgfb2 that encodes an upstream ligand of the TGF-β signaling pathway, by suppressing its promoter activity. Our results suggest that the CAD risk gene PRDM16 is highly expressed in VSMCs and is a novel regulator of VSMC homeostasis and neointima formation.

Cushing syndrome (CS) from metastatic adrenocortical carcinoma (ACC) or neuroendocrine tumors (NETs) presents a therapeutic challenge when surgery is not feasible. Liver-directed embolization, including bland transarterial embolization (TAE) and yttrium-90 (Y-90) radioembolization, may palliate hypercortisolism arising from hormonally active hepatic metastases. We conducted a retrospective single-center case series of 4 adult patients (≥18 years) with CS and liver-dominant metastatic ACC or NET who underwent hepatic embolization between 2015 and 2025. Inclusion criteria were: (1) confirmed CS based on standard biochemical testing, and (2) receipt of liver-directed embolization (TAE or Y-90) for hypercortisolism. Exclusion criteria were absence of pre- and postembolization hormonal data preventing biochemical assessment. The primary outcome was biochemical response within 14 days (≥50% reduction or normalization of morning cortisol). Secondary outcomes included duration of biochemical control, radiographic response (RECIST 1.1), and adverse events (CTCAE v5.0). Four patients (2 ACC, 2 NET) underwent Y-90 (n = 1) or TAE (n = 3). All achieved significant cortisol; 2/4 normalized cortisol with transient adrenal insufficiency. The Y-90 patient had sustained remission, while 2 TAE patients achieved partial hormonal control enabling tapering of medical therapy. Radiographically, tumor burden stabilized or improved in most treated lesions. Embolization was well tolerated, with only 1 case of post-embolization syndrome and no procedure-related mortality. One patient died from disease progression; 3 remain alive with controlled or improving disease. Hepatic embolization is a viable palliative option for CS due to unresectable liver-dominant metastases, providing meaningful biochemical improvement with acceptable safety and supporting integration into multidisciplinary CS management.

Distinct pathways of disease progression with dual checkpoint blockade versus immunotargeted therapy in metastatic renal cell carcinoma.

Delandistrogene moxeparvovec is a recombinant adeno-associated virus rhesus isolate serotype 74 vector-based gene therapy that addresses the absence of functional dystrophin in Duchenne muscular dystrophy (DMD). EMBARK is a phase 3, two-part, crossover, randomized, placebo-controlled trial assessing the safety and efficacy of delandistrogene moxeparvovec (single intravenous dose 1.33 × 1014vector genomes/kg) in ambulatory male patients with DMD aged 4 to < 8years; N = 125. One-year results demonstrated the manageable safety of delandistrogene moxeparvovec, consistent with previous clinical trials. The primary endpoint (change from baseline in North Star Ambulatory Assessment [NSAA] total score at 52weeks compared with placebo) did not meet statistical significance. However, key secondary endpoints, comprising timed function tests, suggested slowing or stabilization of disease progression with delandistrogene moxeparvovec, which could become increasingly evident over longer periods of time. We report 2-year follow-up of safety and functional outcomes in patients receiving delandistrogene moxeparvovec in EMBARK part1. As a result of the crossover study design, 2-year functional outcomes of patients receiving delandistrogene moxeparvovec in part1 of EMBARK were compared, by pre-specified analysis, with a matched propensity score-weighted external control (EC). At 2years, EMBARK patients showed statistically significant benefit versus the EC cohort in functional outcomes prognostic for delaying loss of ambulation (NSAA, Time to Rise, 10-m Walk/Run), demonstrating sustained stabilization or slowing of disease progression. Delandistrogene moxeparvovec micro-dystrophin expression and sarcolemmal localization were maintained over 64weeks. No new safety signals were observed between week52 and week104. Between baseline and week104, there were no treatment-related deaths, study discontinuations due to adverse events, or clinically significant complement-mediated adverse events. At 2years, stabilization or slowing of DMD disease progression was observed in ambulatory male patients with DMD aged 4 to < 8years receiving delandistrogene moxeparvovec versus a matched EC cohort. Safety was consistent with EMBARK 1-year data and manageable with appropriate monitoring. GOV: NCT05096221.

Clinical and Genetic Characterization of CAPN3-Related Limb-Girdle Muscular Dystrophies in an Egyptian Cohort.

Homologous recombination deficiency (HRD) has emerged as a key vulnerability in selected cancer types and is associated with response to platinum and PARPi-based treatment strategies. However, additional biomarkers and targeted therapy options are needed to broaden the range of patients that could benefit from this therapeutic niche. Here, we show that the SARC-HRD signature, composed of ten genes of the homologous recombination repair pathway, stratifies a cohort of sarcoma patients, and associates with genomic biomarkers of HRD, with disease progression and with the CINSARC prognostic signature. Equivalently to CINSARC, high levels of SARC-HRD are associated with poor metastasis-free survival, underscoring the potential of SARC-HRD to predict disease outcome. By pharmacotyping patient-derived cell models, we identified promising drug targets within the DNA damage response (DDR) for sarcoma with HRD traits. Inhibition of ATR, CHK1 and WEE1 elicited synthetic lethality in sarcoma cells with HRD, which concomitantly showed an upregulation of ATR signaling. Combinatorial drug testing further revealed synergistic drug combinations between ATRi, WEE1i, PARP1/2i and chemotherapeutic agents with potential clinical impact. Mechanistically, targeting ATR signaling at multiple levels induced a replication defect, mitotic abnormalities and apoptotic cell death. Taken together, our results demonstrate the therapeutic benefit of targeting DDR mechanisms in sarcoma with HRDness traits and their potential clinical utility for treating a broader spectrum of tumor types.

Metabolomic signaling in sarcoidosis pathogenesis.

A timeline of structural and functional consequences to ipRGCs in a mouse model of Alzheimer's disease.

A novel method using electronic health record coding to generate a unique, multipurpose database for aerodigestive malignancy surveillance.

Guizhi Gegen Decoction alleviates influenza-associated intestinal injury by balancing lung-gut ILC2 distribution via the S1P/S1PR1 axis.

Bone is a highly dynamic tissue undergoing continuous remodelling through the coordinated actions of osteocytes, osteoblasts and osteoclasts. This process is tightly regulated by key signalling pathways, including the RANK/RANKL/Osteoprotegerin system, which governs bone resorption and formation. In addition, the CXCL12/CXCR4 axis and G-protein-coupled receptor 4 (GPCR4) play crucial roles in bone development, remodelling, and pathological conditions such as cancer progression. Skeletal metastases arise from complex interactions between tumour cells and the bone microenvironment, facilitating arrest, extravasation, and colonisation at secondary sites. In osteosarcoma and metastatic cancers, these molecular mechanisms contribute to tumour growth, bone degradation, bone formation and disease progression. This review highlights the intricate crosstalk between bone remodelling pathways and tumour cell invasion, providing insights into potential therapeutic targets for osteosarcoma and bone metastases.

Microbiome alterations and host-pathogen interactions in paratuberculosis: A one health perspective.