Citations

ABSTRACT Cataract is a leading cause of visual impairment worldwide, and its prevalence is increasing with population aging. The majority are age‐related cataracts (ARC), clinically classified into nuclear, cortical, and posterior subcapsular cataracts (PSC) by opacity location. Mechanisms of cataractogenesis remain incompletely understood. While cortical and nuclear cataracts are largely attributed to crystallin aggregation, such protein‐centric mechanisms fail to explain the early onset and axial location of PSC. Morphologically, PSC resembles posterior capsule opacification (PCO), a secondary cataract driven by epithelial–mesenchymal transition (EMT) of lens epithelial cells (LECs), suggesting LEC‐EMT may also contribute to PSC. Using clinically stratified human lens samples, we confirmed EMT marker expression across PSC subtypes. Transcriptomic profiling revealed that LECs, the lens's sole metabolically active cells, in age‐related PSC (ARC‐PSC), compared with age‐related nuclear cataract (ANC) and clear lenses, exhibit elevated EMT signatures tightly linked to senescence‐associated inflammatory signaling. Aqueous humor (AqH) profiling demonstrated a pro‐inflammatory milieu across PSC subtypes, with IL‐17A uniquely elevated in ARC‐PSC, consistent with transcriptomic findings. Integrated analyses support a model in which senescence functions as an upstream driver, whereby senescent LECs release SASP factors, including IL‐17A, that activate NF‐κB signaling to amplify inflammation, reinforce senescence, and drive EMT. In vitro, senolysis and IL‐17A blockade disrupted this loop, attenuating senescence‐ and EMT‐associated phenotypes. Collectively, our study demonstrates that senescent LECs sustain an IL‐17A–NF‐κB circuit that drives EMT and accelerates ARC‐PSC progression, positioning ARC‐PSC as a unique human context to study senescence‐induced epithelial remodeling in aging tissues.

Immunotherapy has been effective in many cancer types but has failed in multiple clinical trials in prostate cancers, with the underlying mechanisms remaining largely unclear. Here, we demonstrate that androgen receptor pathway inhibitor (ARPI) plus irradiation (IR) triggered robust anticancer immunity in prostate cancers in both patients and mice. We show that androgen-activated AR suppressed innate immune signaling by inducing inhibitor of nuclear factor kappa-B kinase subunit epsilon ( IKBKE ) gene repression through HDAC2 interaction with an IKBKE enhancer RNA ( IKBKE eRNA, or IKBKE-e ). ARPI treatment caused IKBKE derepression and enhanced an IR-induced innate immune response via action of RIG-I and MDA5 dsRNA sensors. IKBKE-e ablation largely enhanced innate immunity in prostate cancer cells in culture and anticancer immunity in mice. Our results revealed AR, HDAC2, and IKBKE eRNA as critical intrinsic immune suppressors in prostate cancer cells, suggesting that rejuvenating inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKKε) signaling by targeting IKBKE-e is an actionable strategy to elicit synthetic anticancer immunity in immunologically “cold” cancers such as prostate cancer.

Abstract: AIM: The purpose of this study is to investigate the safety and effectiveness of remote ischemic conditioning (RIC) as a therapeutic intervention for cerebral ischemia in patients with Takayasu arteritis (TA). METHODS: TARIC-1 is a randomized, double-blind, parallel-group pilot trial conducted at Xuanwu Hospital, Capital Medical University. Participants with TA and reduced cerebral blood perfusion are randomly allocated to either the RIC or sham-RIC groups. Both the groups receive conventional medical care, with the RIC group receiving twice-daily sessions of 200 mmHg inflation pressure and the sham-RIC group receiving 60 mmHg inflation pressure, for 24 consecutive weeks. OUTCOMES: The primary outcome is the change in mean cerebral blood flow across the entire brain and regions of interest following the 24-week RIC treatment. Secondary outcomes include clinical assessments using the Indian Takayasu Clinical Activity Score 2010, Vasculitis Damage Index, and Birmingham Vasculitis Activity Score at 24 weeks postintervention. Changes in arterial transit time and the incidence of major adverse cerebrovascular events are additional secondary outcomes. Safety outcomes include mortality and any adverse events, including skin changes and pain ratings, within the 24-week period. SAMPLE SIZE ESTIMATES: This pilot study plans to enroll 22 patients per group, totaling 44 participants. CONCLUSIONS: In individuals with TA, RIC may be a well-tolerated treatment that enhances cerebral perfusion and lowers the risk of ischemic cerebrovascular episodes. TRIAL REGISTRATION: http://www.clinicaltrials.gov (identifier: NCT06178419).

PURPOSE Manual extraction of treatment outcomes from unstructured oncology clinical notes is a significant challenge for real-world evidence (RWE) generation. This study aimed to develop and evaluate a robust natural language processing (NLP) system to automatically extract cancer treatments and their associated RECIST-based response categories (complete response, partial response, stable disease, and progressive disease) from non–small cell lung cancer (NSCLC) clinical notes. METHODS This retrospective NLP development and validation study used a corpus of 250 NSCLC oncology notes from University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center, annotated by physician experts. An end-to-end NLP pipeline was designed, integrating a rule-based module for entity extraction (treatments and responses) and a machine learning module using biomedical clinical bidirectional encoder representations from transformers for relation classification. The system's performance was evaluated on a held-out test set, with partial external validation for relation extraction on a Mayo Clinic data set. RESULTS The NLP system achieved high overall accuracy. On the UPMC test set (64 notes), the relation classification model attained an area under the receiver operating characteristic curve of 0.94 and an F1 score of 0.92 for linking treatments with documented responses. The rule-based entity extraction demonstrated a macro-averaged F1 score of 0.87 (precision 0.98, recall 0.81). Although precision was high for chemotherapy and most response types (1.00), recall for cancer surgery was 0.45. External validation at Mayo Clinic showed moderate relation extraction F1 scores (range: 0.51-0.64). CONCLUSION The proposed NLP system can reliably extract structured treatment and response information from unstructured NSCLC oncology notes with high accuracy. This automated approach can assist in abstracting critical cancer treatment outcomes from clinical narrative text, thereby streamlining real-world data analysis and supporting the generation of RWE in oncology.

Abstract Background Dual‐contrast imaging of iodine and bismuth has shown promise in previous phantom and animal studies utilizing spectral CT. However, these studies often employed Pepto‐Bismol containing bismuth subsalicylate with dosages exceeding the recommended limits for human consumption, limiting their clinical applicability. Purpose The purpose of this study was to improve iodine–bismuth dual‐contrast imaging on a clinical photon‐counting CT (PCCT) system using a noise‐optimized virtual monoenergetic imaging (VMI) approach. Methods Four bismuth samples (0.6, 1.3, 2.5, and 5.1 mg/mL) and three iodine rods (1.0, 2.0, and 5.0 mg/mL) were inserted into a multi‐energy CT phantom and scanned on a PCCT system at 140 kV. VMIs were generated from 40 to 190 keV in 10 keV increments. Iodine and bismuth maps were computed for all possible keV pairs using a generic image‐based three‐material decomposition method and compared with maps generated from the original low‐/high‐energy PCCT images. Mass concentrations, noise levels, and individual as well as joint root‐mean‐square error (RMSE) for iodine and bismuth were measured to determine the optimal keV pair. The contrast‐to‐noise ratios (CNRs) of low concentration samples (bismuth: 0.6 and 1.3 mg/mL; iodine: 1.0 mg/mL) were calculated at the optimal keV pair and compared to the values determined with the original PCCT images. In an IRB‐approved feasibility study, a research patient was administered two doses of Pepto‐Bismol prior to a routine abdomen‐pelvis CT scan. Material decomposition was performed using both the original low‐/high‐energy images and the optimal VMI pair identified in the phantom study. Bismuth signals in the stomach and proximal small bowel were assessed qualitatively and quantitatively. Results The VMI pair of 110 and 190 keV was determined to be optimal, achieving the lowest joint RMSE of 0.49 mg/mL, compared to 1.42 mg/mL for the original low‐/high‐energy pair. It also yielded the highest CNR, representing a 190–318% improvement over the original low/high‐energy decomposition. Qualitatively, both phantom and patient studies demonstrated improved iodine–bismuth separation and reduced noise using the optimized VMI pair. Conclusions These findings suggest that noise‐optimized VMI selection can enhance dual‐contrast material decomposition performance on clinical PCCT, supporting its potential for translation into gastrointestinal imaging applications.

ABSTRACT Most brain organoids derived from human induced pluripotent stem cells (iPSCs) lack microglia and thus immune function. Microglia‐like cells (MGCs) can be differentiated from iPSCs, while the characteristics of isogenic MGC‐containing brain organoids in modeling neurodegeneration and cell‐cell communications have not been well investigated. In this study, iPSC‐derived MGCs are co‐cultured with isogenic forebrain cortical organoids (iFCo), which are stimulated with extracellular vesicles (EVs) of brain organoids differentiated from Alzheimer's disease (AD) patient‐derived iPSCs ( APOE ε4/ε4 and presenilin 1). The AD EV‐stimulated co‐culture organoids are treated with EVs from healthy MGCs or co‐culture. Differential responses of the co‐cultured organoids and the MGCs to AD EVs are demonstrated. The co‐cultured organoids mitigated pro‐inflammatory gene expressions. EVs from healthy MGCs or co‐culture reduced the expression of IL‐12β , iNOS , TREM2 , and CASS4 , which are associated with neural inflammation and degeneration, as well as showed regulation on genes involved in microglial activation and carbon metabolism. AD EV cargo analysis by proteomics and microRNA‐sequencing revealed APOE and APP proteins and microRNAs regulated pathways such as mitophagy. This study paves the way for understanding the role of microglia and brain organoids in modeling neural degeneration and the development of EV‐based cell‐free therapeutics for AD treatment.

Abstract Pseudouridine (Ψ) is the most prevalent RNA modification in human cells. Although Ψ was among the first post-transcriptional modifications discovered (1951), its biological functions remain poorly understood. More recently, Ψ was incorporated into COVID-19 mRNA vaccine, where it enhances RNA stability and reduces innate immune sensing. However, the precise roles of RNA Ψ in cancer, including leukemia, are largely unknown. Here, we identify RNA Pseudouridine Synthase D4 (RPUSD4) as a novel vulnerability in acute myeloid leukemia (AML) via directly catalyzing mitochondrial RNA (mt-RNA) Ψ formation. We further provide proof-of-concept evidence that targeting RPUSD4 suppresses leukemogenesis and stimulates anti-leukemia immunity. To investigate whether RNA Ψ dysregulation is involved in leukemia, we first compared RNA Ψ levels between primitive CD34+ cells (LSC-enriched) and CD34- bulk cells from multiple primary AML specimens. CD34+ AML cells exhibited significantly elevated RNA Ψ levels. We also examined Ψ levels across various RNA types in AML cells, identifying that mt-RNA contained much higher Ψ levels than other RNA types. These findings imply that RNA Ψ, particularly mt-RNA Ψ, may play a role in LSC biology and leukemogenesis. Further unbiased CRISPR screening revealed RPUSD4 as the most critical Ψ synthase for LSC maintenance. Large-scale transcriptomic and patient data analyses showed that RPUSD4 is highly expressed in AML specimens (P = 3.5 × 10-9), particularly within LSCs (P = 1.4 × 10-18). RPUSD4 knockout (KO) significantly suppressed AML proliferation, reduced mitochondrial OxPhos, and decreased LSC frequency in vitro and substantially delayed AML progression in vivo (MLL-r and FLT3ITD models). Of note, RPUSD4 KO-mediated anti-leukemia effects could be fully rescued by wild-type but not catalytically inactive RPUSD4 both in vitro and in vivo, demonstrating that Ψ synthase activity is essential for its function in leukemia. To profile RPUSD4-dependent Ψ sites, we applied two orthogonal technologies, direct nanopore sequencing and PRAISE sequencing (PMID: 36997645), both capable of detecting Ψ at single-base resolution. These approaches converged on a single RPUSD4-dependent Ψ at position 3,067 on mt-16S rRNA. This Ψ site is essential for maintaining rRNA stability. RPUSD4 KO induced mt-16S rRNA decay, thereby suppressing mitochondrial translation. This led to OxPhos inhibition, growth suppression, and LSC eradication in AML. Mechanistically, RPUSD4 is exclusively localized in mitochondria, where it directly interacts with the mt-RNA exonuclease PNPase. Under physiological conditions, PNPase resides within mitochondria and degrades mt-RNA to prevent accumulation of mitochondrial double-stranded RNA (mt-dsRNA). Upon RPUSD4 depletion, PNPase translocates from mitochondria to the cytosol, resulting in two major consequences: (i) mRNA decay:Cytosolic PNPase degrades mRNAs, particularly the nuclear-encoded mitochondrial mRNAs, such as DHODH(Dihydroorotate dehydrogenase). By retrogradely upregulating DHODH, RPUSD4 promotes de novo pyrimidine synthesis in AML. (ii) Aberrant mt-dsRNA accumulation: The buildup and cytoplasmic release of mt-dsRNA activates “viral mimicry” response that sensitizes AML cells to T cell cytotoxicity. Finally, to therapeutically target RPUSD4, we developed an RNA-based inhibitor, CpG-siRNARPUSD4, by conjugating a specific RPUSD4 siRNA to a Toll-like receptor (TLR9) ligand. CpG-siRNARPUSD4 is specifically internalized by TLR9+ cells, including AML cells, thereby maximizing selectivity and minimizing toxicity. Preclinical studies demonstrate that pharmacologically targeting RPUSD4 significantly prolonged survival across multiple AML models, including patient-derived xenograft (PDX) models, and rendered AML cells more susceptible to T cell–mediated cytotoxicity. Furthermore, the RPUSD4 inhibitor exhibited a promising synergistic effect with DHODH inhibitor in treating relapsed AML in vivo. For instance, in a representative relapsed PDX model, median survival times (in days) were: Ctrl – 28, RPUSD4 inhibitor – 36, DHODH inhibitor – 39, and combination – over 60. In conclusion, our findings uncover a previously unrecognized role of RPUSD4 and mt-RNA Ψ in leukemic metabolism, anti-leukemia immunity, and LSC maintenance. This study also bridges a critical knowledge gap regarding the role of RNA Ψ in leukemogenesis.

Importance The Breast Cancer Index (BCI) previously identified premenopausal patients with tumors in which the ratio of expression of HOXB13 relative to IL17BR (hereafter, BCI [H/I]–low tumors) as likely to derive greatest benefit from ovarian function suppression (OFS)–containing adjuvant therapy in the Suppression of Ovarian Function Trial (SOFT) trial. Objectives To assess BCI as a predictive biomarker of benefit from exemestane plus OFS vs tamoxifen plus OFS and to validate BCI as a prognostic biomarker for premenopausal patients. Design, Setting, and Participants This prognostic study used a prospective-retrospective translational design within the Tamoxifen and Exemestane (TEXT) and SOFT trials (enrolled November 2003 to April 2011). Blinded BCI testing in all available tumor samples was completed in March 2024. Premenopausal women with hormone receptor–positive breast cancer randomized to tamoxifen plus OFS or exemestane plus OFS who had BCI assessed were included. Analysis occurred from March to August 2024. Exposure 5 years of adjuvant tamoxifen plus OFS or exemestane plus OFS. Main Outcomes and Measures The primary outcomes were breast cancer-free interval (BCFI) for predictive analyses and distant recurrence-free interval (DRFI) for prognostic analyses after a median follow-up of 13 years in the TEXT cohort. Secondary objectives examined the predictive performance of BCI (H/I) in the combined TEXT and SOFT cohort overall and in prespecified clinical subgroups. Results Of 1782 patients in the TEXT study, 1034 (58.0%) had BCI (H/I)–low tumors; 915 (51.3%) of patients had N0 disease and 1077 (60.4%) were younger than 45 years. Patients with BCI (H/I)–low tumors had a 6.6% absolute benefit in 12-year BCFI (HR, 0.61; 95% CI, 0.44-0.85) for exemestane plus OFS vs tamoxifen plus OFS, while those with BCI (H/I)–high tumors had a 6.3% absolute benefit (HR, 0.78; 95% CI, 0.57-1.07; P for interaction = .29). Results were consistent in the combined TEXT plus SOFT cohort (2896 patients) and adjusting for clinicopathological variables. Clinical subgroup analyses consistently showed benefit of exemestane plus OFS vs tamoxifen plus OFS for BCI (H/I)–low tumors, and more variable relative treatment effects among BCI (H/I)–high tumors, including by age. Post hoc exploratory time-varying estimates suggested the treatment × BCI associations may differ in years 0 to 5 vs greater than 5 years. BCI and BCI N+ as continuous indices were prognostic for distant recurrence in N0 (HR, 1.27; 95% CI, 1.11-1.44; P < .001) and N1 (HR, 1.58; 95% CI, 1.21-2.05; P < .001) cancers. The 12-year DRFI was 96.3%, 90.3%, and 84.9% for BCI low-, intermediate-, and high-risk N0 cancers, respectively. Conclusions and Relevance In this study of premenopausal women with hormone receptor–positive breast cancer, BCI (H/I) status did not clearly predict greater benefit of adjuvant exemestane plus OFS vs tamoxifen plus OFS for women with BCI (H/I)–low tumors than for those with BCI (H/I)–high tumors; BCI continuous indices were reconfirmed as prognostic for premenopausal women. These findings support prior results of SOFT, which compared tamoxifen-alone vs OFS with either exemestane or tamoxifen, indicating premenopausal patients with BCI (H/I)–low tumors may benefit from more intensive endocrine therapy.

Abstract » The coronal plane alignment of the knee (CPAK) classification is a practical and straightforward framework to define a patient’s constitutional coronal knee limb alignment and joint line obliquity. » Patients are assigned to one of nine phenotypes using two straightforward calculations; the arithmetic hip-knee-ankle angle (aHKA) and the arithmetic joint line obliquity (aJLO). » CPAK allows clear understanding of the geographical and gender variations in knee alignment, as well as the differing outcomes of knee reconstructive surgery, based on phenotype. » CPAK enables surgeons to tailor their alignment strategy to best fit a patient’s constitutional phenotype and avoid the drawbacks of a “one-size fits all” approach.

Abstract Background Although there are data describing the onset of neurocognitive toxicity following radiation for patients with brain metastases, less is known about the potential for functional cognitive recovery (CR). This study sought to evaluate CR following neurocognitive function failure (NCF) in patients treated with stereotactic radiosurgery (SRS), whole-brain radiotherapy (WBRT), and hippocampal avoidance (HA)-WBRT. Methods A pooled analysis of 3 (NCCTG N107C/CEC.3, NCCTG N0574, and NRG CC001) clinical trials was performed. Patients with trial-defined NCF and longitudinal cognitive testing were included. The primary endpoint was time to CR, defined as patients no longer exhibiting a 1 or more standard deviation decline from baseline on any cognitive test. Results A total of 288 patients were included, with a median follow-up of 12.2 months. The cumulative incidence of CR was 38% (95% confidence interval [CI] = 32.5% to 43.9%) at 6 months after NCF. Incidence of CR was significantly improved with post-op SRS vs WBRT (hazard ratio [HR] = 2.68, 95% CI = 1.43 to 5.03, P = .002) and with SRS vs SRS+WBRT (HR = 2.35, 95% CI = 1.16 to 4.79, P = .008). On multivariable analysis, SRS was highly prognostic of CR compared with WBRT (HR = 2.42, 95% CI = 1.70 to 3.45, P < .0001). Meta-analysis demonstrated that conformal RT techniques (SRS or HA-WBRT) conferred a significantly higher rate of CR compared with WBRT (pooled HR = 2.12, 95% CI = 1.49 to 3.02, P < .001); 68% of patients had long-term sustained CR. Conclusions A sizeable proportion of patients who experience NCF following brain radiation eventually attain full and sustained CR, thereby highlighting that neurocognitive decline may not be permanent. The use of conformal radiation techniques results in greater rates of neurocognitive recovery.