Citations

Abstract Background Sarcopenia is common in chronic obstructive pulmonary disease (COPD) and contributes to adverse outcomes. Alpha-1 antitrypsin deficiency (AATD) is the most common genetic cause of COPD, but its impact on skeletal muscle remains to be determined. Methods We performed a retrospective analysis of 487,207 participants in the UK Biobank with available SERPINA1 genotyping. Associations between AAT genotypes and measures of skeletal muscle mass were determined using multivariable linear and logistic regression models. Models adjusted for age, sex, smoking status, genetic principal components, lung function (FEV₁% predicted), and liver fibrosis risk (FIB-4). We determined that the Z-allele was associated with sarcopenia and mortality using regression models and mediation analysis. Results Compared with PI*MM individuals, carriers of the Z allele (PI*MZ, PI*SZ, PI*ZZ) demonstrated significantly lower fat free mass index (FFMI) and appendicular skeletal muscle index (ASMI), as well as higher odds of sarcopenia by binary definition. Associations persisted after adjustment for lung and liver function. A dose-dependent relationship was observed, with the greatest reductions in muscle mass and highest sarcopenia associated with PI*ZZ individuals (adjusted OR for FFMI-defined sarcopenia 2.02, 95% CI 1.16-3.32). Each additional Z allele was associated with increased mortality risk (adjusted OR 1.09, 95% CI 1.02-1.16), with sarcopenia mediating a modest proportion (∼2.6%) of this association. Conclusions. The SERPINA1 Z allele is associated with reduced muscle mass and increased risk for sarcopenia independent of lung and liver disease. Our findings expand the phenotypic spectrum of AATD-related diseases to include skeletal muscle as a modifiable target for intervention.

Diffuse B-cell lymphomas are the most prevalent canine hematologic malignancies, and their clinical presentation resembles that of human B-cell non-Hodgkin lymphomas (NHLs). However, a lack of a clear subtyping framework perpetuates imprecise treatment approaches that fail to address mechanisms of therapy resistance. Here, we employed deep phenotyping via serial sampling and longitudinal transcriptomics to evaluate intratumoral composition and therapy response in a 6-year-old neutered male goldendoodle with stage 5A marginal zone lymphoma (MZL). Following sequential treatment consisting of a single IV dose of oncolytic vesicular stomatitis virotherapy (VSV) and standard CHOP chemotherapy 30 days later, we performed scRNAseq on seven serial lymph node biopsies and spatial sequencing on a resection taken 10 days post-VSV treatment. B cells (>90%) comprised three transcriptionally distinct and temporally stable subpopulations, with specific copy number profiles and robust spatial organization despite disrupted lymph node architecture. Analysis across subpopulations revealed downregulation of the quiescence program including KLF2, suggesting similarity to KLF2-deficient human MZL. While VSV successfully reached target B cells, downstream transcriptional responses were predominantly localized to the T-cell compartment. T cells (≤6%) showed increased proliferation and upregulation of cytotoxicity markers post-VSV administration, enriching for leukocyte-mediated cytotoxicity pathways consistent with an anti-viral immune response. Ultimately, these results provide an in vivo proof-of-concept for the treatment paradigm in canine lymphoma, while emphasizing the need for improved subtyping frameworks and multidimensional treatment strategies targeting intratumoral heterogeneity.

Early-onset colorectal cancer (eoCRC) is increasing globally, raising interest in modifiable dietary exposures that may contribute to its development. High fructose intake, particularly from sugar-sweetened beverages and high-fructose corn syrup, has been associated with colorectal neoplasia and eoCRC in epidemiologic studies. Experimental evidence suggests that fructose may promote colorectal tumorigenesis through enhanced uptake and metabolism, polyol pathway activation, glycolytic and lipogenic reprogramming, hypoxic adaptation, and interactions with the tumor microenvironment. Excess fructose reaching the colon may also impair intestinal barrier integrity and alter gut microbial composition and metabolite production. Preclinical models support a direct tumor-promoting effect of fructose independent of obesity, whereas human mechanistic and microbiome data remain limited. This review summarizes current evidence linking fructose exposure with eoCRC and discusses emerging metabolic, microbial, and translational implications, while highlighting key gaps that must be addressed to establish causality and clinical relevance.

Autosomal dominant polycystic kidney disease (ADPKD), mainly driven by pathogenic variants in PKD1 and PKD2 , is the most common inherited cause of kidney failure. Details of ADPKD pathogenesis are incompletely resolved, but primary cilia are an integral component. There is also evidence for changes to the tubular basement membrane (TBM) in early disease. In this issue of the JCI , Mazloum and colleagues link cilia-dependent, PKD1-mediated regulation of the TBM to ADPKD pathogenesis. Using in vivo, ex vivo, tubule-on-chip, and cellular models of ADPKD, they connect cilia-dependent tubule dilation and TBM thinning to early-stage cystogenesis. Moreover, they identify a cilia-dependent TBM remodeling expression signature in affected tubules and suggest that PC1 loss compromises TBM stiffness. By integrating roles for cilia at the apical membrane and extracellular matrix at the basolateral membrane in cystogenesis, this work highlights the TBM as an additional area for investigation of therapeutic and biomarker discovery in ADPKD.

Aging occurs heterogeneously across organs, leading to progressive tissue dysfunction. Cellular senescence is a stress response triggered by age-associated insults, yet the mechanisms regulating senescence and organ aging remain incompletely understood. Here, we defined a role for lysine-specific demethylase 1 (LSD1) in DNA damage–mediated senescence and organ aging. LSD1 was upregulated in aged organs and senescent cells. In response to natural aging or ionizing radiation–induced DNA damage, LSD1 interacted with and demethylated ATM at lysine 3,016, as confirmed using a newly generated ATM-K3016me antibody. This modification sustained ATM phosphorylation, amplified DNA damage signaling, and delayed checkpoint recovery, promoting senescence and organ aging. Inhibition of LSD1 accelerated ATM dephosphorylation via WIP1, enhanced DNA repair, reduced senescence and DNA damage, and prevented irradiation-induced hair graying. Elimination of senescent cells with senolytics reduced LSD1 protein in aged organs, indicating a feedback loop between LSD1 and senescence. Mechanistically, LSD1 underwent autophagosome-lysosome degradation through interaction with LC3 and Beclin1, and autophagy impairment during DNA damage contributed to LSD1 accumulation in senescent cells. This study revealed LSD1 as a key regulator of DNA damage–induced senescence and organ aging and suggested that targeting LSD1 may attenuate senescence, delay organ aging, and prevent hair graying.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited disorder leading to kidney failure. Tolvaptan, the only FDA-approved therapy, modestly slows disease progression but is limited by significant adverse effects, highlighting the need for more effective and better-tolerated treatments. Ciliary polycystins are central to ADPKD pathogenesis. We previously demonstrated that a cilia base-localized pool of CDK6 restricts ciliary polycystin abundance by suppressing axonemal polyglutamylation. However, whether CDK6 inhibition can restore polycystin function and suppress ADPKD progression in vivo remains unknown. Methods: Abemaciclib was tested in in vitro 3D cyst assays and ex vivo metanephric organ cultures. In vivo efficacy of early- and late-stage intervention were assessed in F1(129/B6) Pkd1 R3277C/R3277C mice receiving daily abemaciclib. Tolvaptan served as a therapeutic control. Cyst burden, fibrosis in the kidneys, kidney function, and primary cilia of renal epithelial cells were analyzed at study endpoints. Results: CDK6 was prominently upregulated in cyst-lining cells in human and murine PKD kidneys. At doses substantially lower than those used in oncology, abemaciclib robustly suppressed cyst growth in vitro and ex vivo . In vivo , long-term early treatment arrested cyst progression more effectively than tolvaptan without detectable toxicity. Late intervention largely halted cyst growth in females and reversed cyst progression in males. Mechanistically, abemaciclib restored axonemal polyglutamylation and increased ciliary polycystin levels. Conclusions: Abemaciclib has greater therapeutic efficacy and tolerability than tolvaptan in this preclinical model, largely driven by CDK6 inhibition–mediated restoration of axonemal polyglutamylation and increased ciliary polycystin abundance.

ABSTRACT Chronic liver disease (CLD) is a major cause of global morbidity and mortality, with outcomes closely linked to the severity of liver fibrosis. While liver biopsy has historically been the reference standard for fibrosis staging, its invasiveness, sampling variability and limited suitability for longitudinal monitoring have driven the widespread adoption of non‐invasive tests (NITs). Imaging‐based biomarkers, particularly elastography, now play a central role in the clinical assessment and care pathway design. This review focuses on imaging techniques for non‐invasive assessment of liver fibrosis, with emphasis on elastography techniques: vibration‐controlled transient elastography (VCTE), ultrasound‐based shear wave elastography (SWE) and magnetic resonance elastography (MRE). Technical principles, advantages, limitations and implementation considerations are discussed to support informed selection across clinical contexts. VCTE offers rapid point‐of‐care assessment with extensive validation for identifying advanced fibrosis but is limited by operator dependence, reduced repeatability and lack of anatomical information. SWE provides real‐time, radiologist‐controlled assessment with improved applicability in obesity and ascites, though intervendor variability and operator dependence remain challenges. MRE demonstrates the highest diagnostic accuracy, reproducibility and technical success, with assessment of larger liver volume and strong performance across etiologies, albeit with limited access due to the requirement of an MRI system. Adjunct MRI biomarkers, including proton‐density fat fraction and iron‐corrected T1 mapping, further enhance liver phenotyping by characterising steatosis and fibro‐inflammatory activity. Understanding the strengths and limitations of each technique is essential for radiologists supporting multidisciplinary CLD management and service implementation, particularly in evolving healthcare environments such as Australia.

Abstract To review key concepts in facial nerve anatomy, physiology, injury mechanisms, and recovery patterns, and to summarize current approaches to classification, evaluation, and management of facial nerve dysfunction following skull base surgery. Narrative review of anatomical, clinical, and evaluative frameworks relevant to facial nerve dysfunction. Academic and clinical contexts involving the assessment and management of facial nerve injury, with emphasis on skull base surgery. Not applicable; this is a literature-based review. Descriptions of facial nerve anatomy and microanatomy; established classification systems for facial nerve injury; mechanisms of injury; patterns of recovery; common clinical presentations of post-surgical facial paralysis; and current grading scales and evaluation protocols. The review synthesizes foundational anatomical principles with contemporary understanding of facial nerve injury and recovery. It outlines the full spectrum of clinical outcomes observed after facial nerve injury, including typical post-surgical paralysis patterns and their natural course. Commonly used facial paralysis grading scales are compared, and standardized evaluation strategies are highlighted to promote consistent assessment across providers. Taken together, the findings provide a comprehensive framework for understanding and evaluating facial nerve dysfunction following skull base surgery. Understanding and treating facial nerve dysfunction requires nuanced knowledge of anatomy, injury mechanisms, recovery trajectories, and standardized evaluation methods. Consolidating these elements offers valuable guidance for skull base surgeons, facial plastic surgeons, and other clinicians caring for patients with facial paralysis, and supports more consistent and informed clinical decision-making.