Citations

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.

Objective To assess the effect of Moses™ 2.0 (Lumenis Be Ltd., Yokneam Illit, Israel; Boston Scientific, Marlborough, MA, USA) for lithotripsy of renal stones of 8–20 mm in diameter on operative time, surgeon workload, and retropulsion. Subjects/Patients and Methods In our multicentre, randomised, double‐blind clinical trial, patients were randomised 1:1 to standard or Moses 2.0 laser lithotripsy and stratified by stone size. Patients and surgeons were blinded to laser modality. Primary outcomes were total operative time as well as surgeon workload assessed by the National Aeronautics and Space Administration‐Task Load Index (NASA‐TLX). Secondary outcomes were stone retropulsion evaluated by blinded video review and postoperative clinical outcomes. Linear regression modelling was used for analysis. Results A total of 153 patients (79 Standard, 74 Moses 2.0) with similar clinical, stone, and operative characteristics were evaluated. There was no significant difference in operative times between the Standard and Moses 2.0 groups ( P = 0.73). Moses 2.0 was associated with lower effort, frustration, mental, physical, and temporal workload, as well as higher rated overall performance compared to the standard laser. Video review demonstrated no difference in rates of retropulsion ( P = 0.13). Complication rates (Standard: 13%; Moses 2.0: 10%) and stone‐free rates (Standard: 51%; Moses: 2.0 55%) were comparable. Conclusion Our study evaluated the impact of Moses 2.0 technology on high‐powered renal stone dusting, constituting the largest double‐blind trial of its kind to date. There was insufficient evidence to suggest any difference in operative times or clinical outcomes when using Moses 2.0 compared to standard laser lithotripsy. Moses 2.0 was associated with reduced surgeon workload, which has implicit impact on surgeon wellness.

Aberrant activation of the Hippo–YAP/TAZ–TEAD transcriptional axis is a recurrent feature of multiple solid tumors and contributes to tumor maintenance, lineage plasticity, and therapeutic resistance. Recent medicinal chemistry has shown that TEAD proteins are druggable, but the rate at which in silico screening nominates compounds that prove functionally active in cells remains poorly defined, and negative validation results are rarely reported. Here we describe an experimental assessment of a focused set of computationally nominated candidate compounds, selected from a structure-guided virtual screen of the YAP–TEAD interface across approximately 917,000 library compounds and three predicted binding sites. Candidates were evaluated using long-term (144 hour) CellTiter-Glo proliferation assays in three Hippo-altered malignant pleural mesothelioma cell lines (MSTO-211H, NCI-H2052, NCI-H226), with the validated TEAD inhibitor K-975 and cisplatin as positive controls, and an exploratory TEAD-responsive luciferase reporter in MCF7 cells. K-975 produced dose-dependent antiproliferative activity in MSTO-211H and NCI-H2052, with reduced sensitivity in NCI-H226, while cisplatin reduced viability in all lines. In contrast, the computationally nominated compounds, including AG-690/36549045, AN-655/40856217, and additional library members, did not produce measurable antiproliferative activity at the concentrations tested. In the exploratory reporter, apparent suppression of TEAD activity consistently co-occurred with loss of cell viability, a pattern consistent with cytotoxicity rather than selective transcriptional inhibition; no TEAD-active reference compound was co-tested within the reporter panel, and no direct YAP–TEAD biochemical or target-engagement assay was performed. These results describe a case in which computational nomination at the YAP–TEAD interface showed limited concordance with cell-based activity and provide a transparent account of negative findings to inform expectations for early-stage discovery targeting Hippo-dependent transcriptional programs.

Abstract Background Women remain underrepresented in alcohol use disorder (AUD) research despite sex- and gender-specific health disparities and barriers to treatment. Community-engaged approaches can identify opportunities for patient-centered comparative effectiveness research (CER) that reflect women’s lived experiences. The WomenWise project used community engaged, bi-directional, partnered learning sessions (PLS) to qualitatively explore women’s perspectives on alcohol misuse, treatment barriers, and priorities for future CER. Methods In 2025, we conducted five 90-minute PLSs via Zoom with attendees who were aged ≥ 18 years, self-identified as a woman, reported lived experience of alcohol misuse, were a family member/caregiver of a woman with AUD, and were affiliated with a WomenWise partner organization or a healthcare provider treating AUD. Moderated PLSs focused on bi-directional knowledge exchange and sharing of experiences. Audio transcripts, Zoom chat content, and one asynchronous online discussion thread were analyzed using reflexive thematic analysis. Suggested future CER topics generated during sessions were presented to the WomenWise community advisory board (CAB), which ranked priority topics by vote. Results In total, 51 attendees shared their experiences. The major themes centered on a sense of shame and stigma unique to women, with many attendees mentioning gendered norms, “mom culture,” “quiet drinking,” and caregiver role strain. Barriers to treatment included structural challenges, poor healthcare provider communication, the need for trauma-informed care, and concerns about privacy particularly in rural areas. Six future CER topics emerged, of which the CAB selected three priorities: (1) harm reduction/moderation versus abstinence-only approaches, (2) trauma-focused care versus standard AUD treatment, and (3) care access and engagement strategies. Conclusions These bidirectional, co-learning sessions identified patient-centered, community-informed priorities for future AUD research in women. The findings highlight the importance of addressing stigma, trauma, structural barriers, and provider communication when designing future women-centered treatment studies and care models.

Purpose To assess the reliability, predictability, and discriminative capacity of 3 anatomic measurements, tibial tubercle‐trochlear groove (TT‐TG), tibial tubercle‐posterior cruciate ligament, and patellar tendon‐lateral trochlear ridge (PT‐LTR), where PT‐LTR may offer a complementary approach to assessing recurrent patellofemoral instability (PFI) risk. Methods Patients diagnosed with PFI before primary patellofemoral stabilization surgery at a single institution between 2022 and 2024 were included. A control group without PFI was propensity matched 1:1 for age, sex, and laterality. Magnetic resonance images were evaluated to measure TT‐TG, tibial tubercle‐posterior cruciate ligament, and PT‐LTR. A priori power analysis determined the cohort size. Statistical analyses compared differences between the PFI and control groups with Student t‐tests, receiver operating characteristic analyses, and area under the curve with resultant sensitivity, specificity, and an optimal cutoff. Results Patients included 50 knees with PFI (28 women, 22 men; mean age 18 ± 5 years). The control group included 50 knees (27 women, 23 men; mean age 18 ± 4 years). Excellent inter‐ and intra‐rater reliability (intraclass correlation coefficient > 0.7) was shown for TT‐TG and PT‐LTR in the PFI and control groups. The distances for TT‐TG, tibial tubercle‐posterior cruciate ligament, and PT‐LTR were significant predictors ( P ≤ .025) of PFI. The average PT‐LTR distance difference for the PFI and control groups was 7.0 mm ( P < .001). PT‐LTR showed an area under the curve of 0.80 and, when ≥4.6 mm, was 66% sensitive and 92% specific for PFI. Conclusions The PT‐LTR distance is a reliable and discriminative metric for identifying PFI in both pediatric and adult populations. A PT‐LTR cutoff value of 4.6 mm showed diagnostic discrimination and substantially high specificity for recurrent PFI, indicating strong ability to identify patients with instability. Level of Evidence Level III, retrospective case control study.