Browse Articles

Accelerated CRISPR/Cas12a‐Based Point‐of‐Care Diagnostics Through Critical Coupling Distance Control

ABSTRACT Prompt pathogen detection in resource‐limited settings remains constrained by energy‐intensive instrumentation and a shortage of trained personnel. The CRISPR/Cas12a‐based diagnostic technology, despite its robustness as a promising tool, is constrained by suboptimal detection speed and sensitivity. Here we designed triblock DNA‐mediated spherical nucleic acids (tSNA) that acts as a spatially confined reporter with critical coupling distances between substrates, enabling Cas12a protein to rapidly identify concentrated and stretched single‐stranded substrates with size‐matching intervals. Precise control of distances on tSNA of varying sizes revealed a direct correlation between trans‐cleavage efficiency and coupling distance, indicating that only when the distance exceeds the protein size can it offer an appropriate reaction space. It demonstrates a rapid “scooting” reaction model on tSNA, resulting in a trans‐cleavage rate of 10 nm A30‐tSNA 12 times faster and a sensitivity that is two orders of magnitude higher than that in bulk solution. Furthermore, tSNA can serve as a novel recognition and colorimetric element in lateral‐flow strips, thereby reducing the detection time for pathogen nucleic acids to just 3 min. This “size‐matching” model of tSNA offers a new perspective on the regulation of Cas12a enzymatic activity, establishing a versatile platform to advance diagnostic development through ultrafast, CRISPR‐powered POC systems.

A Bio‐Orthogonal Engineered Chitosan Platform for Enhanced Mesenchymal Stem Cells Delivery and Function in Peripheral Nerve Repair

ABSTRACT Chitosan‐based mesenchymal stem cell (MSC) therapy strategies present a promising approach for peripheral nerves repair following injury. However, the therapeutic efficacy of MSCs is significantly hindered by low cell viability and suboptimal retention at the implantation site. Herein, a bio‐orthogonal strategy that covalently integrates MSCs with chitosan for nerve regeneration is presented. In vitro analysis revealed covalent combination enhanced adhesion and survival of MSCs on chitosan scaffolds via phosphoinositide 3‐kinase (PI3K) and protein kinase B (Akt) signaling pathway. Quantitative proteomics confirmed that these MSCs enhance the secretion of key neurotrophic factors for neuroregeneration. In vivo investigations utilizing a nerve crush injury model demonstrated that bio‐orthogonal‐mediated MSC therapy markedly improves cell retention at the lesion site. Furthermore, this innovative strategy actively modulates the immune microenvironment, accelerates Wallerian degeneration, promotes angiogenesis, and remodels the extracellular matrix, thereby expediting repair processes following peripheral nerve injury. Specifically, further evaluation utilizing a 10 mm sciatic nerve transection model demonstrated that the bio‐orthogonal strategy significantly enhanced the therapeutic efficacy of MSCs. Collectively, the approach developed in this study provides a simple, efficient, and translatable strategy for augmenting MSC‐mediated peripheral nerve repair. This work lays a solid theoretical foundation for the future clinical application of chitosan‐MSC composite materials in neuroregenerative medicine.

A-type lamins anchor emerin at the inner nuclear membrane via two independent binding sites

Gemcitabine Intravesical System Plus Cetrelimab or Cetrelimab Alone as Neoadjuvant Therapy in Muscle-Invasive Bladder Cancer: SunRISe-4 Primary Analysis and Biomarker Results

PURPOSE Standard of care for muscle-invasive bladder cancer (MIBC) is radical cystectomy (RC) with neoadjuvant cisplatin-based chemotherapy (NAC). However, many patients are ineligible for or refuse cisplatin. SunRISe-4 (ClinicalTrials.gov identifier: NCT04919512 ) is an open-label, multicenter, parallel-cohort phase II study assessing neoadjuvant gemcitabine intravesical system (TAR-200/gem-iDRS) plus cetrelimab or cetrelimab monotherapy in patients with MIBC. METHODS Adults with Eastern Cooperative Oncology Group performance status 0-1, cT2-T4a N0M0, ineligible/refusing NAC, and planned for RC were randomly assigned 5:3, stratified by transurethral resection of bladder tumor completeness (residual tumor ≤3 cm permitted) and T stage, to receive TAR-200 plus cetrelimab (cohort 1) or cetrelimab monotherapy (cohort 2). The primary end point was pathologic complete response (pCR) at RC. Secondary end points included recurrence-free survival (RFS) and safety. Exploratory end points included pathologic overall response (pOR; ≤ypT1N0) and circulating tumor (ct) and urinary tumor (ut) DNA molecular residual disease (MRD). Side-by-side descriptive efficacy summary was planned. RESULTS At the May 9, 2025, data cutoff, 159 patients were treated; 88 in cohort 1 and 46 in cohort 2 underwent RC. pCR, pOR, and 1-year RFS rates were 38%, 53%, and 77% in cohort 1 and 28%, 44%, and 64% in cohort 2, respectively. pCR rates were consistent across subgroups. No new safety signals were observed. Across cohorts, utDNA– status before RC (week 12) and utDNA clearance correlated with pCR ( P < 10 –5 and < 10 –3 , respectively). ctDNA– status at baseline and week 12 was associated with longer RFS compared with ctDNA+ status at the same time point ( P = .04 and 0.01, respectively). CONCLUSION TAR-200 plus cetrelimab provided higher pCR, pOR, and 1-year RFS rates compared with cetrelimab monotherapy, supporting further investigation of the neoadjuvant combination in MIBC. utDNA and ctDNA MRD results support further investigation as biomarkers for residual local and nonlocal disease, respectively.

Clinical utility of circulating tumor DNA profiling in patients with metastatic urothelial carcinoma treated with enfortumab vedotin.

798 Background: Enfortumab vedotin (EV) is a key drug for metastatic urothelial carcinoma (mUC). However, no established biomarkers have been identified to predict treatment response or prognosis in EV therapy. Recently, circulating tumor DNA (ctDNA) has attracted attention as a promising biomarker. The aim of this study was to evaluate the clinical utility of ctDNA in patients with mUC treated with EV. Methods: This was a multicenter, retrospective study conducted as part of the tumor-agnostic genomic profiling project MONSTAR-SCREEN2 . Among 151 patients with mUC enrolled, 81 received EV monotherapy, and 60 patients who underwent ctDNA analysis just prior to EV administration were included in this study. All patients underwent both tumor tissue sequencing and ctDNA analysis prior to EV treatment. Tumor tissue sequencing was performed using the MI Profile (Caris Life Sciences), and ctDNA was analyzed with the Caris Assure (Caris Life Sciences). Progression-free survival (PFS) and overall survival (OS) were evaluated using the log-rank test. Results: The primary site was the bladder in 36 patients and the upper urinary tract in 22 patients. A total of 139 variants were identified through ctDNA analysis in 46 patients (76.7%). Of these, 31 variants were derived from clonal hematopoiesis (CH), with a median allele frequency (AF) of 1.5% (IQR 1–5%). Excluding CH, a total of 108 variants were identified in 43 patients (71.7%). The most frequent substitutions were TP53 (36.7%), KMT2D (23.3%), ARID1A (10%), and RB1 (6.7%). The median interval between tumor for sequencing and ctDNA sampling was 388 days (IQR 211–769). Tumor based sequencing identified 243 variants (239 substitution mutations and 4 fusion genes), and 61 mutations were shared between DNA derived from tumor tissue and ctDNA. Patients harboring ≥3 ctDNA mutations had a significantly shorter PFS compared with those with ≤2 mutations (p = 0.040, hazard ratio [HR]: 2.14, 95% CI: 1.02-4.48). A trend toward shorter overall survival was also observed in patients with ≥3 mutations compared with those with ≤2 mutations (p = 0.062, HR: 2.27, 95% CI: 0.94-5.49). In addition, patients achieving disease control (DC: CR + PR + SD) had significantly lower ctDNA AF than those without DC (median 1.3% vs. 7.45%, p = 0.029). Conclusions: The ctDNA profile prior to EV treatment was associated with treatment outcomes and prognosis in mUC, suggesting its potential as a clinically useful biomarker. Association between number of ctDNA substitution variants at pre-EV administration and prognosis. Interquartile Range Progression-free survival (days) Strata Median Lower Upper p-value Number of ctDNA variants <=2 (n=40) 234 141 Not available 0.040 　 >=3 (n=20) 78 50 Not available 　 Interquartile Range Overall survival (days) Strata Median Lower Upper p-value Number of ctDNA variants <=2 (n=40) 751 423 Not available 0.062 　 >=3 (n=20) 205 113 Not available 　

Vertebral surgery in the management of complex postchemotherapeutic retroperitoneal lymph node dissection (PC-RPLND).

610 Background: The involvement of the skeletal system is rare in patients with metastatic testicular germ cell tumors (mGCT). Only about 3-5% of patients demonstrate involvement of the vertebral spine either by solitary metastases or due to continuous infiltration by retroperitoneal lymph nodes. We report on a consecutive series of 14 patients who underwent interdisciplinary surgery to resect residual vertebral metastases at time of postchemo RPLND and to improve oncological outcome. Methods: We retrospectively reviewed our consecutive series of 495 post-chemo RPLNDs from 2017 to 2025 and we identified14 patients who underwent both postchemo RPLND and resection of solitary or oligometastases to the vertebral bodies. The surgical approach was standardized with all patients undergoing a 2-stage procedure: dorsal stabilization followed by thoracoabdominal or transperitoneal resection of the residual retroperitoneal masses with resection 1-2 vertebral bodies in the same session. Vertebral bodies were replaced by carbon composite cages. Complications were evaluated according to Clavien-Dindo classification; oncological outcome was evaluated in terms of progression-free, cancer-specific and overall survival. Results: Median age was 24.9 (18-39) years, all pts had ECOG performance status 0-1. mGCT patients presented with good, intermediate and poor prognosis in 14%, 43% and 43%, resp., and received 3 to 4 cycles PEB. Tumor marker were normalized or plateaued in 86% and 14%, resp. Median operation time for the first session was 2.5 (2-3.5) hours; median OR time for the second session was 8.7 (6-11) hours. 5 patients required adjunctive surgeries with nephrectomy and aortic replacement in 3 and 2, resp. Median blood loss was 650 (320 – 2500) ml with 3 pts requiring red blood cell transfusions. Mean length of hospital stay was 9.8 (7-32) days. Clavien-Dindo grade 3a/b developed in 3 (21%) patients; no grade 4/5 complication and no neurological deficits were observed. Histology of the resected lymph nodes revealed viable cancer, teratoma and fibrosis in 2, 12 and 0 pts, resp. The bone specimens revealed no viable disease, but teratoma or malignant somatic transformation in 9 pts. Median follow-up is 34 (6-55) months. Overall and cancer specific survival is 100% and progression-free survival is 86%. Conclusions: The approach of en bloc surgical resection of residual retroperitoneal and vertebral metastases from mGCT is feasible and it associated with good oncological outcome associated with low surgery associated morbidity. Evaluation of complete surgical resectability, advanced experiences in skeletal and retroperitoneal surgery are essential preconditions for acceptable oncological and functional outcome.

Association of <i>MUTYH</i> mutations with clinical outcomes in metastatic prostate cancer.

83 Background: Identification of novel biomarkers that can better predict treatment outcome and prognosis in metastatic hormone sensitive prostate cancer (mHSPC) is needed. An independent study of 34 mHSPC patients treated at the University of Miami from 11/1/21 to 12/31/24 who underwent tumor sequencing via liquid biopsy revealed a significant association between mutant MUTYH and both shorter overall survival (OS) and time to castration resistance (TTCR). MUTYH is a DNA repair gene involved in base-excision repair of oxidative DNA damage. Based on the results of this discovery cohort, we hypothesized that mHSPC patients with mutant MUTYH will have shorter OS and TTCR compared to patients with wild-type MUTYH . Methods: This study used the nationwide (US-based) de-identified Flatiron Health-Foundation Medicine prostate cancer clinico-genomic database (FH-FMI CGDB), originating from approximately 280 US cancer clinics (~800 sites of care). Patients with advanced prostate cancer treated with ARPI (Androgen Receptor Pathway Inhibitor) or taxanes chemotherapy in the mHSPC setting and genomic profiling, by tissue or liquid NGS testing (minimum 1% ctDNA tumor fraction), were included. Differences among genomically-defined patient groups were evaluated with Cox PH models and visualized with Kaplan-Meier plots. Results: Of 6101 patients with mHSPC with longitudinal clinical data and NGS testing in the database, 4285 were excluded for not having treatment with either ARPI or taxane chemotherapy in the mHSPC setting and 414 for having tumor fraction &lt; 1%. In the remaining 1402 patients included, 851 were treated with single-agent ARPI and 551 were treated with taxane chemotherapy without ARPI. Results of the univariate and multivariate Cox PH models are shown in the table. The multivariate models controlled for pre-treatment prognostic features including PSA, ECOG performance status, and socioeconomic status. Conclusions: The association between MUTYH mutation status and TTCR and OS in mHSPC observed in the University of Miami cohort was not validated in FH-FMI CGDB cohort in either the ARPI group or the taxane group. Additionally, no significant association was uncovered when accounting for potential confounding variables. Further investigation is ongoing to identify genomic signatures of prognostic value in mHSPC. Hazard Ratio (95% CI) p-value TTCR on ARPI 1.39 (0.72, 2.7) 0.331 TTCR on taxanes 1.46 (0.65, 3.27) 0.36 OS on ARPI 1.1 (0.49, 2.48) 0.814 OS on taxanes 1.56 (0.7, 3.52) 0.279 TTCR on ARPI (multivariate analysis) 1.55 (0.79, 3.04) 0.207 OS on ARPI (multivariate analysis) 1.32 (0.58, 2.98) 0.506

Multi‐State Probabilistic Computing Using Floating‐Body MOSFETs Based on the Potts Model for Solving Complex Combinatorial Optimization Problems

ABSTRACT Probabilistic computing has gained attention for solving combinatorial optimization problems (COPs), mainly using the Ising model, which may not be suitable for complex COPs. Instead, this work proposes a multi‐state probabilistic computing system based on the Potts model using stochastic threshold switching floating‐body metal‐oxide‐semiconductor field‐effect transistors (FB‐MOSFETs) as the multi‐state probabilistic bits (p‐bits) to solve challenging COPs. The system employs drain voltage sharing and a one‐hot sampling method to achieve controllable probabilistic behavior and scalable annealing. Experimental validations on spin glass and max‐4‐cut problems demonstrate that the system efficiently samples a tunable Boltzmann distribution while converging faster than traditional methods. Comparative analyses further highlight superior energy efficiency and decreased time‐to‐solution, underscoring the potential of multi‐state probabilistic computing for large‐scale, complex COPs using only MOSFET devices.

Targeting EphA2 under DNA damage causes mitotic bypass via p21 induction

Adjuvant pembrolizumab plus belzutifan versus pembrolizumab for clear cell renal cell carcinoma (ccRCC): The randomized phase 3 LITESPARK-022 study.

LBA418 Background: Adjuvant pembrolizumab is a standard of care for patients with ccRCC at increased risk of recurrence following nephrectomy based on the phase 3 KEYNOTE-564 study (N Engl J Med 385:683; N Engl J Med 390:1359). Combination strategies may further improve outcomes in this setting. We present results from the phase 3, double-blind LITESPARK-022 study (NCT05239728) of pembrolizumab + belzutifan vs pembrolizumab + placebo in pts with ccRCC at increased risk of recurrence post nephrectomy. Methods: Pts had ccRCC stage M0 and intermediate-high (pT2 Gr 4 or sarcomatoid, or pT3 any Gr, N0) or high (pT4 any Gr, N0, or any pT and Gr, N+) risk of recurrence after nephrectomy, or ccRCC stage M1 with no evidence of disease (M1 NED) after surgery. Pts were randomized 1:1 to receive 9 doses of IV pembrolizumab 400 mg Q6W (~1 year) with either oral belzutifan 120 mg QD or placebo. The primary endpoint was DFS by investigator. Secondary endpoints included OS (key) and safety. Results are presented from the first interim analysis (IA1; after 87% of DFS events occurred with a minimum of 15 mo of follow-up). Results: Overall, 1841 pts were randomized (921 to pembrolizumab + belzutifan and 920 to pembrolizumab + placebo). As of Aug 23, 2025, median follow-up was 28.4 mo (range, 15.0–40.1). Pembrolizumab + belzutifan significantly improved DFS vs pembrolizumab + placebo (HR 0.72, 95% CI 0.59–0.87; P = 0.0003). Median DFS was not reached in both arms; estimated 24-mo DFS rate was 80.7% (95% CI, 77.7–83.2) vs 73.7% (95% CI, 70.6–76.6), respectively. OS was immature at IA1 with a total of 87 OS events (38 in the pembrolizumab + belzutifan arm vs 49 in the pembrolizumab + placebo arm) and did not reach statistical significance (HR 0.78, 95% CI 0.51–1.19; P = 0.1220) at 29% of the events needed for final OS analysis. 70% of the pembrolizumab + belzutifan arm and 71% of the pembrolizumab + placebo arm completed the assigned treatment. Among treated pts, grade ≥3 treatment-emergent AEs occurred in 52.1% of pts who received pembrolizumab + belzutifan and 30.2% who received pembrolizumab + placebo, most commonly anemia (12.1% vs 0.4%), increased ALT (6.4% vs 2.0%), and hypoxia (4.6% vs 0%). Grade 5 treatment-emergent (1.1% vs 1.2%, respectively) and treatment-related (0.3% vs 0.3%) AEs were similar between arms. No new safety signals were seen. Conclusions: Adjuvant pembrolizumab plus belzutifan demonstrated a statistically significant and clinically meaningful improvement in DFS vs pembrolizumab plus placebo in pts with ccRCC at increased risk of recurrence post nephrectomy, with a safety profile consistent with the known profiles of each drug. These results support adjuvant pembrolizumab plus belzutifan as a potential new standard of care in RCC at increased risk of recurrence. Clinical trial information: NCT05239728 .

Turning the tide in recurrent NSGCT: Retrospective insights into TIP vs non-TIP salvage chemotherapy.

602 Background: Recurrent NSGCT poses a therapeutic challenge and the comparative efficacy data of TIP (Paclitaxel, Ifosfamide and Cisplatin) versus non-TIP regimens is limited. Methods: This retrospective analysis included adult males with recurrent NSGCT treated with second-line salvage chemotherapy (TIP vs non-TIP) between January 2015 and May 2025. Progression-free survival 1 (PFS1) was time from start of therapy to first disease progression or death, while PFS2 was time to progression on second-line therapy or death. Descriptive statistics and Kaplan-Meier analyses were performed. Results: Among 84 patients (median age - 28 years; IQR: 22 – 37 years), 67.9% were from rural areas and 16.7% were self-funded. Smoking and tobacco-chewing were in 14.3% and 27.4%, respectively. Lung metastases were seen in 76.2%. TIP was used in 40 (47.7%) patients (Table 1). Others received triplets like VbIP (11.9%), VIP (10.7%), Gemcitabine-Oxaliplatin-Paclitaxel (2.4%), or doublets like Gem-Ox (15.5%) or Gem-Paclitaxel (11.9%). Twelve (14.3%) lost to follow-up and were excluded from efficacy analysis. At a median follow-up of 87.3 months, median PFS1 was similar between TIP and non-TIP (8.2 vs 7.6 months, p=0.15). TIP showed better median PFS2 (8.2 vs 4.4 months, p=0.015), median OS (33.4 vs 16.9 months, p=0.016) and 5-year OS (43% vs 15%). Toxicity data of 12 (14.3%) patients were missing. Grade &gt; 3 hematological toxicities (78.4% vs 54.3%, p=0.03), pulmonary toxicity (13.5% vs 0%, p=0.024) and febrile neutropenia (43.2% vs 22.9%, p=0.067) were higher with TIP, while hospitalisation rates were similar (18.9% vs 17.1%, p=0.845). Conclusions: TIP improved PFS2 and OS but caused higher hematologic and pulmonary toxicity. Further prospective validation is needed. Baseline demographic characteristics. Characteristics Non-TIP (n = 44) TIP (n = 40) p-value Age group (years) 0.240  &lt; 35 29 (65.9%) 31 (77.5%)  &gt; 35 15 (34.1%) 9 (22.5%) ECOG PS 0.867  0-1 41 (93.2%) 36 (90%)  2 3 (6.8%) 4 (10%) Primary site 0.339  Testicular 30 (68.2%) 30 (75%)  Retroperitoneal 6 (13.6%) 7 (17.5%)  Mediastinal 8 (18.2%) 3 (7.5%) IGCCCG risk stratification 0.052  Good 1 (2.3%) 3 (7.5%)  Intermediate 8 (18.2%) 15 (37.5%)  Poor 35 (79.5%) 22 (55%) Sites of metastases  Non-regional lymph nodes 33 (75%) 30 (75%) 1.0  Lungs 38 (86.4%) 26 (65%) 0.022  Liver 12 (27.3%) 10 (25%) 0.813 Teratomatous component 19 (43.2%) 20 (50%) 0.531 First-line chemotherapy 0.198  BEP (bleomycin, etoposide, cisplatin) 18 (40.9%) 24 (60%)  VIP (etoposide, ifosfamide, cisplatin) 20 (45.5%) 10 (25%)  EP (etoposide, cisplatin) 5 (11.4%) 5 (12.5%)  VbIP (vinblastine, ifosfamide, cisplatin) 0 1 (2.5%)  TIP 1 (2.3%) 0 Testicular surgery  High inguinal orchidectomy (HIO) 25 (56.8%) 28 (70%) 0.211  Scrotal orchidectomy 4 (9.1%) 3 (7.5%) 0.792 Retroperitoneal lymph node dissection (RPLND) 12 (27.3%) 17 (42.5%) 0.143 Metastatectomy 12 (27.3%) 10 (25%) 0.813

Effect of a one-time sensitive screening intervention on prostate cancer mortality: The STHLM3 randomized trial.

312 Background: Prostate cancer (PCa) screening remains controversial and further results on the long-term benefits and harms are needed. The population-based STHLM3 trial (ISRCTN84445406) invited men to undergo a one-time screening using both prostate-specific antigen (PSA) and Stockholm3 (a predictive model using clinical variables, blood biomarkers, and polygenic risk). Methods: Between 2012 and 2014, men aged 50–69 years without diagnosis of PCa and residing in Stockholm County, Sweden, were randomized (7:3) to receive invitation for PCa screening or no invitation. Participants provided blood for PSA; those with PSA ≥1 ng/mL also had Stockholm3 performed. Men with PSA ≥3 ng/mL or Stockholm3 risk ≥10 were referred for systematic biopsy. We calculated cumulative risks and risk ratios (RRs) for PCa mortality (primary outcome), all-cause mortality, PCa incidence, and cumulative mean number of PSA tests and biopsies per man after 11.6 years of follow-up, comparing invited and non-invited men (intention to screen, ITS). An instrumental variable analysis was used to estimate the effect of screening participation on PCa mortality. An alpha level of 0.035 was used for the primary outcome. Results: We randomized 240,494 men, 169,621 invited and 70,873 non-invited. Of the invited men, 59,088 (35%) participated. After 11.6 years, 352 PCa deaths occurred in the invited group and 161 in the non-invited group (RR 0.96, 96.5% CI 0.77–1.20). After adjusting for participation, the RR of PCa death with one-time screening was 0.41 (95% CI 0.18–0.91) at 6 years and 0.85 (95% CI 0.39–1.88) at 11.6 years (Table 1). PCa incidence was similar among invited and non-invited men at 11.6 years (risk 73.1 vs. 72.3 per 1000; RR 1.01, 95% CI 0.96–1.07), as was all-cause mortality (risk 115.8 vs. 118.1 per 1000; RR 0.98, 95% CI 0.93–1.04). On average, men took more than 3 PSA tests in both groups (mean ratio 1.03, 95% CI 1.02-1.05); 11.5% and 10.6% of men underwent a prostate biopsy in the invited and non-invited groups, respectively (RR 1.08, 95% CI 1.05-1.11). Conclusions: In a population with high opportunistic testing rates, a single invitation to a sensitive PCa screening did not significantly reduce PCa mortality compared to no invitation after 11.6 years, however effects of mortality improvement from one-time screening were seen at 6 years. Clinical trial information: ISRCTN84445406 . Prostate cancer mortality in the intention-to-screen (ITS) and instrumental variable (IV) analysis. Invited (n = 169,621) Non-invited (n = 70,873) Risk Ratio (95% CI) Analysis Events Risk* (95% CI) Events Risk* (95% CI) P value End of follow-up (11.6 years) ITS 352 2.50 (2.21-2.82) 161 2.60 (2.19-3.07) 0.96 (0.77-1.20) † 0.711 IV - - - - 0.85 (0.39-1.88) 6 years ITS 122 0.73 (0.61-0.87) 66 0.94 (0.74-1.19) 0.77 (0.57-1.04) IV - - - - 0.41 (0.18-0.91) 10 years ITS 327 2.02 (1.81-2.25) 154 2.28 (1.94-2.66) 0.89 (0.73-1.07) IV - - - 0.65 (0.35-1.18) *Per 1000 men. †96.5% Confidence Interval (α = 0.035).

County-level educational attainment and long-term outcomes in older men with prostate cancer: A SEER-Medicare 2009–2017 study.

327 Background: Educational attainment shapes access, treatment, and survivorship in prostate cancer (PC), yet community-level effects remain underexplored. We tested whether residence in low-education counties is associated with prostate cancer-specific mortality (PCSM) and related outcomes in older men with PC. Methods: We analyzed SEER-Medicare (2009-2017) including men aged ≥66 years with incident PC. Low education was defined as counties where &gt;15% of adults lack a high-school diploma. Outcomes were PCSM (primary), cardiovascular events (CVE), cardiovascular mortality (CVm), and all-cause mortality (ACM). Fine-Gray competing-risk and Cox models adjusted for demographics, comorbidities, stage/grade, and treatments. Prespecified subgroup analyses were conducted in non-Hispanic Black (NHB) and urban residents. Results: Median follow-up ranged 3.3-4.5 years among 109,724 complete cases of men (85,516 in high-education and 32,210 in low-education counties). Residence in low-education counties was associated with a higher but not statistically significant risk of PCSM (subdistribution hazard ratio [sHR] 1.06; 95% CI 0.95-1.19; p=0.29). In contrast, low-education residence was associated with higher risks of CVE (sHR 1.04; 95% CI 1.01-1.06; p=0.002), CVm (sHR 1.18; 95% CI 1.12-1.25; p&lt;0.001), and ACM (adjusted HR 1.08; 95% CI 1.05-1.11; p&lt;0.001). Similar trends were observed in NHB and urban populations. Conclusions: Living in counties with lower educational attainment was independently associated with higher cardiovascular and overall mortality after PC diagnosis, with a consistent directional trend toward increased PCSM. Community-level education is a structural determinant of survivorship and a practical target for geospatial outreach to improve outcomes. Association of county level educational attainment with mortality and cardiovascular outcomes across overall, NHB, and urban subgroups. Outcome (Model) Overall (aHR/sHR [95% CI], p) NHB (aHR/sHR [95% CI], p) Urban (aHR/sHR [95% CI], p) PCSM (Fine-Gray) 1.06 (0.95–1.19, p=0.29) 1.08 (0.95–1.23, p=0.25) 1.12 (0.90–1.41, p=0.32) CVE (Fine-Gray) 1.04 (1.01–1.06, p=0.002) 0.98 (0.92–1.05, p=0.53) 1.02 (1.00–1.04, p=0.10) CVm (Fine-Gray) 1.18 (1.12–1.25, p&lt;0.001) 1.08 (0.92–1.27, p=0.36) 1.17 (1.10–1.25, p&lt;0.001) ACM (Cox) 1.08 (1.05–1.11, p&lt;0.001) 1.11 (1.02–1.20, p=0.02) 1.05 (1.02–1.09, p&lt;0.001) Sample sizes: Overall N = 109,724; NHB N = 11,726; Urban N = 93,318. Fine-Gray models account for competing risk of death, and Cox proportional hazards models were used for all-cause mortality. Models adjusted for age, race, marital status, socioeconomic status, rurality, prostate cancer stage and grade, diabetes, hypertension, hyperlipidemia, chronic kidney disease, surgery, radiation, chemotherapy, and prior cardiovascular events.

In Situ Synthesis of Covalent Organic Frameworks Inside Cells for Triggering Ferroptosis and Immunotherapy

ABSTRACT The synthesis of non‐natural polymers inside living systems has become an effective approach for controlling cellular functions and behaviors. However, in situ synthesis of crystalline polymers, such as covalent organic frameworks (COFs), inside cells using dynamic covalent chemistry faces challenges in aqueous environments, crystallization, and functionality. Herein, we present an intralysosomal crystalline polymerization strategy to synthesize COFs inside tumor cells through an acid‐catalyzed imine condensation reaction. The COFs synthesized intracellularly exhibit inherent fluorescence and well‐defined crystalline structures, allowing real‐time monitoring of the synthesis and product characterization. The formation of imine frameworks inside cell lysosomes induces lysosomal damage, activates lysosomal iron, and triggers immunogenic ferroptosis, thus enhancing antitumor immunotherapy. This strategy of intralysosomal crystalline polymerization facilitates the ambient synthesis of COFs, opening avenues for therapeutic polymerization reactions and providing insights into cellular responses to in situ polymer synthesis.

Edge‐Activated Few‐Layer Bismuthene for Ampere‐Level Vanadium Redox Flow Batteries

ABSTRACT Pursuing high‐power‐density all‐vanadium redox flow batteries (VRFBs) is an attractive approach toward large‐scale commercialization in a techno‐economic manner. The suboptimal intrinsic activity of conventional catalysts undermines flow batteries' inherent electrode design flexibility, restricting their current density to the low hundreds of mA cm −2 range and curtailing their technological viability. Here, for the first time, we present a few‐layer bismuthene nanoflake (Bi ene NF) catalyst in the field of redox flow batteries (RFBs). The design strategically exploits the ultra‐high intrinsic reactivity of Bi ene NF's outermost lattice periphery, including individual bismuthene monolayer edges where synergistic nanostructural effects and surface chemistry collectively enhance vanadium redox kinetics and thermodynamics. Notably, this edge‐activated catalytic mechanism demonstrates significant intrinsic activity enhancement over bulk bismuth, effectively addressing the dual challenges of deactivation and ohmic losses in flow battery systems. Accordingly, the fueled VRFB reaps an energy efficiency (EE) of up to 80.51% and a reliable catalyst stability over 10 000 cycles at 0.8 A cm −2 , together with an unprecedented peak power density of 3.047 W cm −2 . The demonstrated performance metrics not only establish new benchmarks for VRFB technology but also provide a generalizable strategy for designing high‐activity nanostructured catalysts in electrochemical energy storage systems.

Matriptase-2-mediated suppression of hepatic hepcidin expression in mice requires hepatocyte neogenin

MRI-targeted biopsy with index lesion ipsilateral or bilateral systematic biopsy in prostate cancer: A multicenter, paired, noninferiority, observational trial.

375 Background: Index lesion-focused ipsilateral systematic biopsy (iSB) may potentially replace systematic biopsy (SB) in the MRI-targeted biopsy plus systematic biopsy (TB+SB) paradigm for prostate cancer, but prospective multicenter validation is limited. Methods: This prospective multicenter trial (NCT06584279) enrolled biopsy-naïve men with prostate imaging reporting and data system (PI-RADS) ≥4 lesions or PI-RADS 3 plus prostate-specific antigen (PSA) density ≥0.15 ng/mL/cm 3 . All underwent MRI-targeted biopsy (≥ 2 cores/lesion) with 12-core SB. Through core-level reclassification, we simulated TB+iSB (targeted cores + ipsilateral systematic cores from the index lesion lobe). Primary outcome was the cancer detection rate (CDR) of clinically significant prostate cancer (csPCa; Grade Group ≥2) with a noninferiority margin of -3%. The secondary outcomes included clinically insignificant prostate cancer (cisPCa; Grade Group = 1) detection and pathological concordance after radical prostatectomy. Results: 564 men (median age, 69 years; median PSA, 7.3 ng/mL) were included. TB+iSB demonstrated a noninferior csPCa CDR versus TB+SB (40.78% vs 42.38%; difference, -1.6%, 95% CI [-2.69, -0.5]), with the 95% CI lower bound not exceeding the -3% noninferiority margin. The CDR of cisPCa with TB+iSB was slightly lower than that with TB+SB (13.83% vs 14.36%; difference, -0.53%, 95% CI [-2.0, -0.92]). Among the 189 surgical patients, pathological concordance was similar between TB+iSB (54.0%) and TB+SB (55.6%); upgrade and downgrade rates were also comparable. Conclusions: This study establishes TB+iSB as a noninferior alternative to TB+SB for csPCa detection, supporting its adoption in MRI-guided biopsy protocols to reduce the procedural burden without compromising diagnostic accuracy. Clinical trial information: NCT06584279 .

ICON trial: Phase I/II trial of inulin gel in combination with ipilimumab and nivolumab in advanced renal cell.

TPS572 Background: The gut microbiome has been shown to impact the safety and efficacy of immune checkpoint inhibitor (ICI) therapy. Fecal microbiota transplantation and probiotics such as Clostridium butyricum have demonstrated promise in enhancing ICI efficacy. Inulin is a plant-derived prebiotic dietary fiber found in chicory root and Jerusalem artichoke that increases levels of Bifidobacterium in the gut. Native inulin undergoes rapid degradation and absorption in the upper GI tract, failing to adequately reach beneficial microbes residing in colon. To address this limitation, we developed a colon-retentive inulin-gel oral formulation. In murine models, our inulin gel significantly enhanced systemic anti-tumor efficacy of αnti-PD-1 therapy and led to decreased rates of immunotherapy induced colitis. A study in healthy volunteers established the tolerability of inulin gel. Based on preclinical data demonstrating enhanced ICI efficacy and favorable clinical tolerability, this clinical trial was designed to evaluate the combination of inulin gel with ipilimumab and nivolumab in patients with advanced clear cell renal cancer. Methods: After an initial safety run-in of 6 patients receiving the combination, patients will be randomized 2:1 to the combination of ipilimumab 1mg/kg + nivolumab 3mg/kg (ipi-nivo) and inulin gel 10g twice daily vs ipi-nivo standard of care therapy. Eligible patients have advanced clear cell or sarcomatoid RCC with no prior systemic anticancer therapy. Adjuvant pembrolizumab is permitted if completed &gt; 6 months prior to study enrollment. Patients must be candidates for ipi-nivo as determined by their treating physician. Performance status of 0-1 and adequate bone marrow, renal and liver function are required. The primary endpoint is the proportion of patients free of progression at 6 months. Secondary endpoints include response rate, overall survival, and incidence of immune related and other toxicities. Correlative objectives include assessment of liquid biopsy and baseline tissue genomic sequencing for prognostic and predictive markers, measuring the change in short chain fatty acid levels in stool and changes in the microbiome. Quality of life will be evaluated by patient reported surveys. We anticipate enrollment of 48 patients. The sample size is not sufficiently large to do a formal hypothesis test between the two randomized arms in the study. We will instead provide a confidence interval for the difference in the response rate and progression free survival between the two arms. The analysis will provide the preliminary data required to consider moving towards a larger randomized trial. Clinical trial information: NCT06866262 .

Androgen deprivation therapy and radiotherapy with or without cabazitaxel in very-high risk localized prostate cancer: First results of the PEACE-2 randomized phase III trial.

LBA307 Background: Long-term androgen deprivation therapy (ADT) combined with radiotherapy is standard in patients with localized prostate cancer, no detectable metastases, and a high-risk of dissemination. Cabazitaxel improves overall survival in patients with metastatic castration-resistant disease. We hypothesized that earlier use of cabazitaxel may prevent the onset of relapse or death. Methods: PEACE 2 (NCT01952223) is a 2x2 factorial design randomized trial for patients with very high-risk localized prostate cancer (defined by at least 2 criteria among: Gleason 8-10, T3/T4 disease (MRI T stage permitted), and PSA &gt;20 ng/mL) and no detectable metastases on conventional imaging. Eligible patients all received standard of care (SOC), which consisted of prostate only fractionated RT (74-78Gy in 37-39 fractions) and 3 years of ADT. Patients were then randomized 1:1:1:1 to receive SOC only (Arm A), SOC + prophylactic pelvic RT (46-50 Gy in 23-25 fractions, Arm B), SOC + 4 cycles of cabazitaxel (20-25 mg/m2/3 weeks x 4 cycles) prior to RT (Arm C), or SOC + both cabazitaxel and pelvic RT (Arm D). The primary endpoint is clinical progression-free survival (cPFS) with death, metastases and proven local relapses as events. Initially 1048 patients were planned to detect a treatment effect corresponding to a hazard ratio of 0.70 (absolute difference of 7.5% in cPFS at 6 years) for both comparisons. The accrual was closed early but the analysis plan was maintained after the target event number was reached (n=247 planned events), hence maintaining statistical power. Interaction was first tested between cabazitaxel and pelvic RT: if no interaction was detected, hazard ratios (Cox, logrank) for cPFS were reported for ADT-RT vs ADT-RT-cabazitaxel. Database was locked in October 2025. Results: Overall, 761 patients were included from 2013 to 2021 (median age: 67y) from 4 EU countries, with 2 (79%) or 3 (21%) risk factors, and they were randomized to receive cabazitaxel (n=381) or not (n=380). Pet-choline was used as part of baseline imaging in 18%. The median follow-up is about 85 months and no interaction was found between cabazitaxel and pelvic RT. There was no improvement of cPFS with cabazitaxel (HR: 1.11 [0.87-1.41]; 6-year cPFS rates: 67.2% vs 71.4%). Overall survival rates were greater than 85% in all arms with also no difference. Grade &gt;2 toxicity was reported in 65% and 47% respectively with or without cabazitaxel. Conclusions: Cabazitaxel does not improve cPFS in very-high risk localized prostate cancer. With very few prostate cancer-related deaths observed during the first decade, data from PEACE-2 challenge our current definition of very-high risk localized prostate cancer, especially when defined using modern imaging. Clinical trial information: NCT01952223 .

ADVANCED-2: Interim efficacy and safety data in BCG-unresponsive participants with high-grade non-muscle invasive bladder cancer.

743 Background: Although patients with Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) have several emerging therapeutic options, there remains a clinical unmet need to improve efficacy, durability of response, and tolerability while obviating the need for radical cystectomy. TARA-002 is a lyophilized biological preparation for intravesical instillation containing inactivated cells of Streptococcus pyogenes (Group A, type 3) Su strain. TARA-002 rapidly enters cancer cells, activating TLR2 and NOD2 to trigger the innate immune response, inflammation, and potential immunogenic cell death. Herein we present interim safety and efficacy data of TARA-002 from the BCG-unresponsive cohort of the ongoing ADVANCED-2 study (NCT05951179). Methods: ADVANCED-2 (Cohort B) is a Phase 2, open-label study to evaluate the safety and efficacy of intravesical TARA-002 in BCG-unresponsive adults ≥ 18 years with high-grade NMIBC CIS (± Ta/T1). Key exclusion criteria include penicillin allergy; history of ≥ T2 bladder cancer, nodal, or metastatic disease; or concomitant prostatic or upper tract urothelial involvement. TARA-002 is delivered intravesically for 2 hours and includes induction (6 weekly doses), reinduction (if persistent disease at 3 months), and maintenance (through 24 months). Response is assessed every 3 months for 2 years. Biopsy is mandated at Month 3. Long-term follow-up is conducted up to 60 months. Safety is monitored throughout the study. The primary endpoint is complete response (CR) at any time defined by the absence of any high-grade recurrence. The key secondary endpoint is duration of response. Results: As of 07-October-2025, 32 BCG-unresponsive participants have been enrolled. Majority of participants were White (84.4%, 27 of 32), non-Hispanic (93.8%, 30 of 32), and male (68.8%, 22 of 32). The median age was 74 years (range: 47 to 92). The majority of participants had a baseline diagnosis of CIS only ie, without concomitant Ta/T1 (75.0%, 24 of 32). TARA-002 demonstrated a 68.4% (13 of 19) CR at any time in evaluable participants. The 6-month CR was 75.0% (9 of 12), the 9-month CR was 50.0% (4 of 8), and the 12-month CR was 37.5% (3 of 8). The salvage rate was 75.0% (6 of 8) with reinduction therapy. Most treatment-emergent adverse events (TEAEs) were mild (CTCAE Grades 1-2) and transient; no participants experienced higher than Grade 3 TEAEs. No participants experienced drug-related serious adverse events (SAEs) or drug-related TEAEs leading to withdrawal or death. Conclusions: In participants with BCG-unresponsive high-risk NMIBC with CIS ± Ta/T1, TARA-002 appears to be well tolerated and demonstrated encouraging efficacy, supporting ongoing accrual of the ADVANCED-2 study. Further follow-up will inform durability of response, and data will be updated based on evaluable time points at the time of the presentation. Clinical trial information: NCT05951179 .