Browse Articles

Microdroplet Intaking Spinning Turbine for Active Radiation Fog Harvesting

ABSTRACT Atmospheric fog harvesting is a sustainable freshwater solution, but efficiently collecting from low‐wind, small‐droplet fogs is challenging due to the low inertia of micron‐sized droplets. Here, we demonstrate the microdroplet intaking spinning turbine (MIST), a bioinspired active fog collector that actively draws in fog‐laden air using rotating samara‐like blades. The rotating blades create a stable low‐pressure zone that actively draws in fog, increasing incident fog flux by 5.8‐fold, and direct droplets into the device's blade contours. An array of biomimetic cactus spines on the blades enhances inertial capture of these microdroplets. Biomimetic drip‐tip structures along the blade edges, combined with centrifugal force, enable rapid drainage of collected water, significantly reducing fluid retention. MIST demonstrates collection efficiency one to two orders of magnitude greater than that of existing surfaces, achieving up to 13.8 L m −2  h −1 in field tests and 96.8 L m −2  h −1 in controlled wind‐tunnel tests. MIST device achieved a specific energy efficiency of 86 L kWh −1 of water, surpassing conventional dehumidification systems under the targeted fog conditions. By actively manipulating airflow, this bioinspired architecture maintains high efficiency across diverse mists under low‐wind conditions, demonstrating broad applicability for defogging, outdoor fog harvesting, and viscous oil fume collection.

Profiling the pancreatic cancer secretome with metabolic glycoengineering

Biopsy patterns following high intensity focused ultrasound as assessed by CAPRA score.

324 Background: Cancer of the Prostate Risk Assessment (CAPRA) score determines the overall risk of recurrence after patients with prostate cancer (PCa) undergo treatment. CAPRA (range 0-10 (highest risk)) is computed from five clinical components: age, PSA, Gleason grade, percent biopsy positive cores, and T-stage, each with distinct point-based thresholds. High-Intensity Focused Ultrasound (HIFU) is used to treat patients with clinically significant (GG2 or higher) focal lesions in one lobe with or without GG1 on the contralateral side. Here we assess biopsy patterns at one-year follow-up using CAPRA. Methods: Men with PCa underwent a pre-HIFU biopsy, HIFU procedure, and a one-year post-HIFU biopsy. Pre- and post-HIFU biopsies included both systematic sampling and targeted sampling of the treated lesion. Clinical CAPRA scores were computed before and after HIFU. The primary outcome was change in CAPRA risk category [Low-Risk (0-2), Intermediate-Risk (3-5), High-Risk (6-10)] for those that had residual disease. The secondary outcome was improvement of post-HIFU CAPRA score by 1 or more points. Descriptive analyses of the CAPRA components associated with residual disease after HIFU were performed. Categorical variables were compared with the chi-square test. Results: 142 men had biopsies before and one year after HIFU. Pre-HIFU CAPRA scores were 21% low-, 69% intermediate-, and 10% high-risk; 40% had negative biopsies of the treated area, 20% had GG1, and 40% had GG2+. For out-of-field recurrence, 69% had negative biopsies, 20% had GG1, and 11% had GG2+. Prior to HIFU, 19% of men with low-, 32% with intermediate-, and 23% with high-risk CAPRA had a positive PIRADS and a high Decipher Genomic Classifier (GC) score. 54% of patients had ≤33% positive biopsy cores pre-HIFU, which increased to 84% post-HIFU, p<0.01. Post-treatment improvements in PSA and tumor volume, as assessed by percent of positive cores, were associated with improvements in CAPRA score, both p<0.01. Post-HIFU CAPRA score improved by 1 or more points for 78% of patients, stayed the same for 11%, and worsened for 11%. 20% with improved CAPRA score had benign or no cancer post-HIFU. Risk category improved at 1 year for 56%. Patients in the low-risk category increased from 21% pre-HIFU to 70% post-HIFU, p<0.01. Patients in the intermediate-risk category decreased from 69% pre-HIFU to 25% post-HIFU, p<0.01. Conclusions: After HIFU, half of patients had a lower CAPRA risk category, and three quarters of patients had reduced CAPRA scores by at least 1 point. While persistent (GG1) and recurrent (GG2+) disease appeared to be common after HIFU, as assessed by Gleason grade infield/outfield recurrence rates, HIFU treatment was associated with a clear decrease in cancer risk as assessed by CAPRA. Post-treatment reductions in PSA and tumor volume were associated with improvements in CAPRA score, while age, T-stage, PIRADS, and GC were not significantly associated.

Structured step-based prehabilitation before radical cystectomy and its impact on postoperative recovery and perioperative burden: Interim analysis of the PRACTICE randomized trial (NCT06806059).

662 Background: Radical cystectomy (RC) is associated with substantial morbidity, functional decline, and impaired quality of life (QoL). Prehabilitation through structured physical activity may enhance surgical resilience, but evidence in uro-oncology is scarce. The ongoing bi-center PRACTICE randomized controlled trial evaluates whether a simple, step-based walking intervention can improve perioperative, functional, and patient-reported outcomes after RC. Methods: Patients scheduled for RC were randomized 1:1 to an intervention group (daily walking goal 8,000–10,000 steps) or a control group without a step target. All participants wore activity trackers from randomization until surgery. Functional performance (six-minute walk test [6MWT], chair-rising test, handgrip strength) and QoL (EORTC QLQ-C30) were assessed 4 weeks and 1 day preoperatively, 1 week postoperatively, at discharge, as well as 3 and 12 months postoperatively. Primary endpoint was perioperative morbidity (Clavien-Dindo≥III); secondary endpoints included ICU admission, transfusion, bowel recovery, analgetic demand and functional/quality-of-life changes. Results: Currently, 32 patients have been enrolled, and data from 25 patients (intervention = 14, control = 11) were available for analysis. Baseline characteristics and surgical parameters were comparable. The intervention group achieved significantly higher preoperative step counts (median 8,474 vs 4,098; p = 0.003). Major complications occurred in 14% vs 36% (p = 0.20). ICU admission (15% vs 73%; p = 0.005) and transfusion rates (8% vs 46%; p = 0.033) were markedly lower in the intervention arm, while length of stay and bowel function were similar. One week after RC, the intervention group showed superior functional recovery with greater 6MWT distance (399 m vs 282 m; p = 0.004) and faster chair-rising time (10.7 s vs 16.8 s; p = 0.009); handgrip strength was comparable. QoL improved in 54% vs 10% of patients (p = 0.029) during the preoperative period. Preoperative step count correlated strongly with postoperative mobility (r = 0.68). No adverse events related to the walking intervention occurred. Conclusions: This interim analysis demonstrates that a simple, wearable-guided walking intervention before RC is feasible, safe, and clinically meaningful. Patients who achieved higher preoperative activity experienced fewer transfusions and ICU admissions, faster functional recovery, and improved QoL. Step-based prehabilitation represents a low-cost, scalable strategy to enhance perioperative outcomes and patient-centered recovery in major uro-oncologic surgery. Clinical trial information: NCT06806059 .

Inclusion of patients from Latin America in pivotal trials in genitourinary (GU) and cutaneous malignancies.

646 Background: Latin America bears an increasing burden of both genitourinary (GU) and cutaneous malignancies but remains underrepresented in trials shaping global standards of care. This gap raises ethical concerns and limits data generalizability. We assessed Latin American (LATAM) representation in landmark GU and skin cancer trials and explored ethical and strategic approaches to enhance equity. Methods: We reviewed practice-changing phase 2/3 trials in advanced GU and cutaneous skin cancers (melanoma, non-melanoma) published from 2015–2024. Data extracted included geographic origin, trial site distribution, and ethnicity reporting. Results: Overall, 46 pivotal trials (26 GU, 17 Skin) including a total of 38,900 patients were analyzed. LATAM sites appeared in 44 trials, but only 25 trials enrolled Hispanic/Latino patients (n = 2,459 patients; 6.3%). All GU trials referenced LATAM participation, though only a subset enrolled patients. Among melanoma studies, 15/17 (88%) mentioned LATAM participation, while 2 (12%) did not. Across the LATAM region, participation was unbalanced: Brazil (16 trials), Argentina (14), Chile (13), Mexico (12), and Colombia (6). Representation was higher in GU trials (Brazil 13, Mexico 10, Argentina 10, Chile 9, Colombia 4) versus skin cancer (Brazil 3, Mexico 2, Argentina 4, Chile 4, Colombia 2). Transparency was limited: only 2 trials reported Hispanic/Latino data in main tables, 5 in supplements, and 23 mentioned it in ClinicalTrials.gov. Conclusions: Only 6% of patients from Latin America were included in pivotal trials of genitourinary and cutaneous malignancies. Barriers likely included infrastructure gaps, regulatory delays, and limited funding. Policies mandating geographic representation, and context-adapted designs are urgently needed to move from intended participation to meaningful inclusion.

A phase I clinical trial of autologous gamma delta T cells genetically engineered with a chimeric receptor to target the prostate stem cell antigen in patients with metastatic castration-resistant prostate cancer.

TPS287 Background: Prostate Stem Cell Antigen (PSCA) is a glycosylphosphatidyl inositol-anchored cell surface protein that is overexpressed in > 80% of prostate cancers and further enriched in prostate cancer bone metastases. Prior phase 1 studies with alpha/beta CAR-T cells targeting PSCA showed feasibility, and preliminary antitumor activities (NCT02744287 and NCT 03873805). To reduce the systemic toxicities, we designed gamma/delta enriched anti-PSCA CAR-T therapy with activation of its T cell receptor by the phosphoantigens induced by bone targeting zoledronate. Based on the anti-tumor activities and synergies with zolendronate observed in preclinical studies (PMID 37134157), we designed and conducted a phase 1 study in heavily pre-treated patients (pts) with metastatic castration resistant prostate cancer (mCRPC). Methods: This is a single center phase 1 dose-escalation trial with the Bayesian optimal interval design to identify the recommended phase 2 dose (RP2D). Safety assessment is the primary objective, and the secondary objective of preliminary efficacy is measured by best PSA response, radiographic progression free survival and conversion of circulating tumor cell count from above 5 per 7.5ml of peripheral blood to <5. Men with mCRPC, adequate organ function, ECOG performance 0-2, and bone dominant metastasis are eligible. At least one line of chemotherapy in the mCRPC setting and intravenous zoledronate treatment within 4 weeks of CAR T infusion are required. Prior treatment with lutetium Lu 177 vipivotide tetraxetan is allowed, if the last dose is given > 3 months of study enrollment. After apheresis on day -14, each enrolled pt undergoes lymphodepletion chemotherapy (LDC) with cyclophosphamide at 500 mg/m2 and fludarabine at 30 mg/m2 on Days -5, -4, -3. Day 0 infusion of Fresh gamma/delta enriched CAR T cells targeting PSCA are being tested at five dose levels: 1 × 10 5 , 3 × 10 5 , 1 × 10 6 , 3 × 10 6 , and 5 x 10 6 CAR T cells/kg. Following determination of RP2D, an expansion phase will be initiated. The dose limiting toxicity (DLT) observation period starts with the administration of LDC and concludes at 28 days following the day 0 CAR T infusion. This study has completed dose level 2 with no DLT observed. The 2nd pt for dose level 3 is scheduled for apheresis. Clinical trial information: NCT06193486 .

Engineered Bacterial Biomaterials for Augmenting Adoptive Immune Cell Therapy Against Solid Tumors

ABSTRACT Adoptive immune cell therapy (ACT) represents one of the most promising strategies in cancer immunotherapy, leveraging genetically engineered immune cells to recognize and eradicate tumor cells with high specificity. Durable remissions have been achieved in hematological malignancies, particularly with CD19‐targeted chimeric antigen receptor T (CAR‐T) cell therapies. However, the efficacy of ACT in solid tumors remains limited due to the immunosuppressive tumor microenvironment, tumor heterogeneity, and poor infiltration and persistence of the effector cells within tumor sites. Bacterial biomaterials, encompassing live bacteria and their acellular platforms, for example, outer membrane vesicles, represent emerging classes of programmable systems capable of reshaping the tumor immune microenvironment. In this review, we briefly illustrate the underlying molecular mechanisms by which bacterial biomaterials remodel the tumor environment and underscore the advances in the use of engineered bacterial biomaterials to enhance the efficacy of ACT in solid tumors, highlighting the underlying basic principles and engineering strategies to augment current adoptive cellular therapies for overcoming their faced dilemmas in solid tumor settings.

Modulation of MOF Energy State to Construct Smart Activated Sensitizers for Membrane Directed C–H Ketene Therapy in Tumor Cells

ABSTRACT Phospholipid oxidation closely links tumorigenesis to tumor microenvironment (TME) remodeling, easily producing lipid peroxides that cause inflammation and membrane damage. The inherent complexity and unpredictable biological effects of phospholipid peroxidation necessitate precision catalytic platforms for selective amplification of specific oxidized lipid species to enable mechanistic studies. We engineered a supramolecular smart composite material, SD‐1@PCN‐Ru, by integrating a ruthenium‐modified metal‐organic framework (MOF) with the receptor tyrosine kinase (RTKs)‐targeting fluorescent probe (SD‐1). This design leverages MOFs’ tunable porosity and catalytic versatility to spatially confine oxidative activity at tumor membranes via RTKs overexpression. Ru‐modified MOFs exhibit enhanced capabilities in photoinduced oxygen activation and electron transfer compared to their pristine counterparts, thereby facilitating phospholipid ketenization. Lipidomics reveals selective depletion of phosphatidylethanolamine (PE) and phosphatidylcholine (PC) at plasma membranes, compromising integrity while generating immunostimulatory oxidized lipids. Concurrently, the excessive reactive oxygen species (ROS) generated by SD‐1@PCN‐Ru activate caspase‐1/3 and GSDMD, thereby inducing immunogenic cell death and remodeling the immunosuppressive TME. In vitro/vivo studies demonstrate tumor‐specific cytotoxicity and growth suppression surpassing non‐targeted analogs, achieved through precision oxidative damage and immune activation. This work pioneers intelligent nanocomposites merging catalytic efficiency with molecular targeting, offering a transformative strategy for lipid peroxidation‐mediated TME modulation via synthetic‐biological integration.

TET2 in epigenetic control of immune cells: Implications for inflammatory responses and age-related pathologies

Clinical outcomes in the real-world utilization of 177Lu-PSMA 617 in metastatic castrate-resistant prostate cancer.

104 Background: 177Lu-PSMA-617 (177Lu) is an established therapy for PSMA-PET–positive metastatic castration-resistant prostate cancer (mCRPC). We used a large US real-world (RW) dataset to describe utilization and outcomes with 177Lu. Methods: mCRPC pts treated with 177Lu from 23-Mar-2022 to 25-Aug-2025 were included in this study from the deidentified Integra PrecisionQ database. Baseline features (age, race, ECOG performance status, Charlson comorbidity index (CCI), prostate-specific antigen [PSA]) and treatment course (follow-up, number of 177Lu cycles) were collected. A landmark analysis at 9 mo after the first 177Lu dose among pts alive and in care assessed predictors of receiving 1-3 vs. 4-6 cycles using logistic regression. Overall survival (OS) from first 177Lu dose was assessed with Cox proportional hazards models adjusted for prespecified baseline covariates. Missing covariates were handled by complete-case analysis. Results: A total of 1002 pts received 177Lu: 718 had ≥9 mo of follow-up at the landmark, of which 109 (15.2%) were treatment-naïve. Median age was 71 yr (range 65-77). Among the 718 pts, median OS was 15 mo (95% CI 13.3-16.8) and 98 (13.6%) received exactly 1 cycle; 95 (13.2%) received exactly 2 cycles; 95 (13.2%) received exactly 3 cycles; 94 (13.1%) received exactly 4 cycles; 69 (9.6%) received exactly 5 cycles, and 267 (37.2%) received exactly 6 cycles. In multivariable analysis, higher baseline PSA (OR 0.77 per ng/mL; 95% CI 0.70-0.85; P<0.001) and greater comorbidity burden (OR 0.84 per 1-point increase in CCI; 95% CI 0.76-0.94; P<0.001) were associated with receiving fewer cycles (1-3 vs. 4-6). Worse OS outcomes were associated with pre-treatment ECOG 3 vs. 0 (HR 4.02, 95% CI 2.20-7.35; P<0.001) and higher log(PSA) (HR 1.30 per 1 unit; 95% CI 1.22-1.38; P<0.001), while longer time from mCRPC diagnosis to 177Lu initiation was associated with lower hazard (HR 0.99 per month; 95% CI 0.99-1.00; P=0.033). Baseline characteristics are summarized in the table. Conclusions: In RW practice, more than one-third of eligible pts completed six 177Lu cycles. Higher baseline PSA and greater comorbidity burden were associated with receiving fewer cycles, underscoring the value of early risk stratification to maximize completion of full treatment courses with 177Lu. Characteristic/Outcome Total 177Lu Cycles (1-3) n=287/718 Total 177Lu Cycles (4-6) n=431/718 P value Age at treatment (Q1, Q3), yr 73 (65, 78) 71.5 (66, 77) 0.0264 PSA (Q1, Q3), ng/mL 88 (22, 337) 28.5 (7.9, 141.7) <0.0001 Hemoglobin (Q1, Q3), g/dL 10.8 (5.7, 16.4) 11.9 (10.9, 13.2) <0.0001 CCI (Q1, Q3)* 8 (8, 10) 8 (8, 9) 0.005 Overall survival (95% CI), mo 6.1 (5.3, 6.7) 21.1 (19.3, 25.1) <0.0001 *Despite similar median and IQR values, the underlying distributions of CCI scores differed significantly between groups (Wilcoxon rank-sum test, P=0.005).

Geographic disparities in the availability of renal cell carcinoma (RCC) clinical trials in the United States (US).

431 Background: Clinical trials for cancer tend to be less available in regions of the US corresponding to high socioeconomic vulnerability (Kirkwood et. al., JCO Oncol Pract 2025); however, specific patterns for RCC have yet to be reported. We aimed to evaluate the current county-level distribution of RCC clinical trials in the US. Methods: Using ClinicalTrials.gov, we identified all interventional trials between 6/1/2019 and 6/1/2025 enrolling adult patients with RCC. Using US Postal Service data, we recorded every unique county for Zip code listed for each trial. Trial characteristics were summarized descriptively. We used the Centers for Disease Control and Prevention (CDC) Social Vulnerability Index (SVI) designations to reflect county demographics and socioeconomic status. Age-adjusted renal cancer incidence and mortality rates were obtained from the National Cancer Institute (NCI). To account for overdispersion of trial availability and high proportion of counties with no trials, we used a zero-inflated negative binomial (ZINB) regression model to assess the association between number of RCC trials per county and corresponding incidence, mortality, and SVI. To account for county size, we adjusted trial rates by number of households. Analyses were performed in R (v.4.4.3) using the “pscl” package. Results: Of 289 eligible trials, 127 (43.9%) enrolled patients with only clear cell RCC and 34 (11.8%) with only non-clear cell RCC. Pharmaceutical companies sponsored the greatest proportion of trials (46.0%), followed closely by academia (43.6%). Most trials (76.1%) enrolled patients with advanced or metastatic disease. Only 672 (21.4%) of all US counties had at least one clinical trial location. Compared with high-SVI counties (most socially vulnerable), those in the medium-high, low-medium, and low-SVI counties had 1.8-fold (95% CI: 1.38-2.36), 2.0-fold (95% CI: 1.50-2.58), and 3.1-fold (95% CI: 2.29-4.13) higher trial incidence rates, respectively (all p < 0.001). Of the 5,028 US trial sites analyzed, 1,681 (33.4%) were in counties with the lowest renal cancer incidence quintile, while only 254 (5.1%) were in counties with the highest incidence quintile. This pattern held for counties with the lowest and highest mortality quintiles, with 1508 (30.0%) and 183 (3.6%) trials, respectively. Conclusions: Most US counties lacked RCC clinical trial representation. Counties with higher social vulnerability had markedly lower RCC clinical trial availability. Social vulnerability reflects census-derived variables such as socioeconomic status, household composition, disability, minority status, English proficiency, transportation, etc. These findings highlight geographic and structural disparities in access to novel RCC therapies within the US, and emphasize the need for trial design and site selection that account for regional vulnerability.

Real-world characteristics of long-term survivors with metastatic castration-resistant prostate cancer (mCRPC) treated with radium-223 (Ra-223): An analysis of the global REASSURE study.

74 Background: Ra-223 is an alpha-emitting radionuclide approved to treat mCRPC with bone metastases. The REASSURE study (NCT02141438) assessed the long-term safety (~10 years [yrs]) and overall survival (OS) associated with Ra-223 in clinical practice. This was the most comprehensive and longest-term prospective study focused on safety and efficacy of a radiopharmaceutical in this setting. Methods: Patients (pts) with mCRPC with bone metastases were enrolled from 2014–2017 (final data cut-off: October 2024). We compared pts with extended OS to those without, using a 2-yr cutoff. We evaluated disease history, baseline characteristics, treatment patterns (including prior, concomitant and subsequent treatments), fracture rates, incidence of second primary malignancies (SPMs), and OS from diagnosis of castration resistance and Ra-223 initiation. Analyses were descriptive. Results: Of 1472 pts, 393 (27%) survived ≥2 yrs (median OS 38.1 months) and 1079 (73%) survived <2 yrs (median OS 10.7 months). Respective median age was 71 and 74 yrs; median time from castration resistance to study entry was 9 and 13 months. The table shows key differences between groups. Pts surviving ≥2 yrs had less advanced disease at Ra-223 initiation and lower disease volume versus those surviving <2 yrs; baseline alkaline phosphatase (median 94 vs 158 U/L), prostate-specific antigen (median 22 vs 89 ng/mL) and lactate dehydrogenase (median 214 vs 294 U/L) were also lower. Fewer pts with extended OS received androgen receptor pathway inhibitors and/or taxanes prior to Ra-223, and nearly all completed Ra-223 therapy. Pts with extended OS tended to receive subsequent treatments and had longer median OS from castration resistance diagnosis (Table). Approximately half of pts used bone protective agents, and the observed rates of fractures (≥2 yrs: 16%, <2 yrs: 7%) and SPMs (≥2 yrs: 4%, <2 yrs: 1%) were low. Conclusions: Pts with the longest survival received Ra-223 treatment earlier, with a majority completing therapy and many subsequently receiving additional life-prolonging therapy, all contributing to extended OS. This highlights the significance of careful patient selection when evaluating the benefits of Ra-223. Statistical methods to identify factors associated with long-term survival will be discussed. Clinical trial information: NCT02141438 . OS ≥2 years (N=393) OS <2 years (N=1079) ECOG PS: 0-1, % 87 77 Extent of Disease: <6 / >20 lesions, % 28 / 13 15 / 23 Abiraterone: Prior / Concomitant / Subsequent, % 39 / 17 / 25 51 / 14 / 6 Enzalutamide: Prior / Concomitant / Subsequent, % 29 / 20 / 36 43 / 17 / 7 Docetaxel: Prior / Concomitant / Subsequent, % 26 / 1 / 35 44 / 2 / 12 Cabazitaxel: Prior / Concomitant / Subsequent, % 4 / 0 / 22 12 / 1 / 7 Bone Protective Agent: Prior / Concomitant, % 54 / 50 48 / 38 Completed 6 Ra-223 injections, % 92 48 OS from time of castration resistant cancer, median, months 56.2 27.4

Germline radiosensitivity biomarker for radiation-induced GU toxicity following radiation therapy in localized prostate cancer (GARUDA): Two-year outcomes of a phase II clinical trial.

359 Background: Stereotactic body radiation therapy (SBRT) is increasingly used for localized prostate cancer, yet treatment-related genitourinary (GU) toxicity remains a concern, with grade ≥2 GU toxicity after SBRT impacting nearly one-third of patients two-years after treatment. PROSTOX, a biomarker based on germline genetic variants, may identify patients who are more likely to experience late grade ≥2 GU toxicity after SBRT. The GARUDA trial prospectively evaluated whether pre-treatment determination of PROSTOX status followed by shared decision-making on treatment choice would lead to lower rates of late grade ≥2 GU toxicity in a cohort of patients that would otherwise receive SBRT. Methods: GARUDA (NCT04624256) was a single-arm, prospective Phase II trial that enrolled patients with localized prostate cancer considering SBRT. Participants underwent PROSTOX testing prior to treatment and were offered SBRT (40 Gy in 5 fractions) or moderately hypofractionated radiotherapy (MHFRT, 60 Gy in 20 fractions). Co-primary endpoints were physician-scored acute and late GI and GU toxicity by CTCAE 4.03 and PROs assessed by the Expanded Prostate Cancer Index-26 (EPIC-26) and International Prostate Symptom Scores (IPSS). Statistical comparisons of stratified proportions are based on Gaussian approximations to Binomial probabilities. This is a secondary endpoint analysis of 2-year toxicity outcomes. Results: Between November 2020 and May 2022, 208 patients were enrolled. Median follow-up was 25 months (IQR: 24–30). Based on PROSTOX, 180 patients (86.5%) were classified as low-risk and 28 (13.5%) as high-risk for late grade ≥2 GU toxicity. Among low-risk patients, 98.6% elected SBRT and 1.4% chose MHFRT; among high-risk patients, 57.1% chose SBRT and 42.9% MHFRT Of those treated with SBRT, 66% received MRI-guided SBRT. The 2-year cumulative incidences of late grade ≥2 GU toxicity for the whole cohort was 18%. At 24 months, 18.1% (26/144) of patients reported a >2-fold minimal clinically important difference in urinary incontinence scores, and 22.9% (33/144) in urinary irritation scores. Mean 24-month changes from baseline were +0.47 for IPSS, -3.1 for EPIC urinary incontinence, -2.53 for urinary irritation, and -3.5 for overall urinary scores. Conclusions: Two-year data from the GARUDA trial support the clinical utility of a germline biomarker in predicting radiation-related GU toxicity. Despite high-dose SBRT being delivered in 93% of patients, the incidence of grade ≥2 GU toxicity at two years was lower than expected. These findings highlight the potential of integrating germline biomarkers into radiation planning for men with localized prostate cancer. Clinical trial information: NCT04624256 .

A Homo‐Triatomic Molybdenum Cluster Catalyst Enables Synergistic Optimization of Multi‐Step Sulfur Reduction Chemistry

ABSTRACT The isolated single‐active sites of single‐atom catalysts (SACs) often suffer from simultaneously maintaining the optimal adsorption states of multiple lithium polysulfide intermediates in sulfur redox reactions of Li–S batteries. Herein, we report a homo‐triatomic molybdenum cluster catalyst with Mo 3 –O 3 N 3 motifs embedded within a carbon matrix (Mo 3 /ONC) that addresses this challenge. The Mo 3 –O 3 N 3 motifs with a triangular configuration feature multi‐active sites and interatomic synergies, which can flexibly adjust the corresponding Mo─S pathway according to different intermediate sulfur species, thereby making the adsorption strength of all species favorable. Meanwhile, the optimized Mo─S interactions can induce more electrons to transfer from the intermediate sulfur species to the Mo 3 –O 3 N 3 catalytic sites, thus weakening the S─S bond and remarkably reducing the energy barriers for the sulfur conversion. Besides, the electrochemical and in situ spectroscopic experiments disclose that the sulfur redox kinetics on Mo 3 /ONC is significantly improved compared to the Mo‐single‐atom catalyst (Mo 1 /ONC) counterpart. As thus, the as‐designed Mo 3 /ONC catalyst renders the Li–S battery with a large rate capability of 661.2 mAh g −1 and a capacity decay as low as 0.027% per cycle at 10 C for 1200 cycles. This work provides a new perspective on the fundamental design principles of triatomic catalysts for improving the Li–S performance.

Development of an inhibitory monoclonal nanobody targeting Streptococcus pyogenes siderophore binding protein FtsB

Discontinuation rates among patients with metastatic castration-sensitive prostate cancer (mCSPC) initiating novel androgen receptor inhibitors in oncology and non-oncology settings.

105 Background: Novel androgen receptor pathway inhibitors (ARPI) apalutamide (Apa), darolutamide (Daro), and enzalutamide (Enza) have demonstrated improved outcomes in mCSPC clinical trials; however, real-world evidence describing treatment patterns is limited. This study assessed the real-world duration of therapy (DOT) and time to discontinuation of ARPIs as doublet therapy across oncology and non-oncology settings. Methods: This retrospective cohort analysis used the IQVIA Real-World Data (Adjudicated US Claims data). Adult men with mCSPC who initiated ARPI treatment as initial treatment between January 1, 2020 and January 31, 2025 were included. Patients receiving concomitant docetaxel were excluded. Discontinuation was defined as a ≥60-day gap following the end of supply. Patients were stratified by care setting at treatment initiation as oncology vs. non-oncology (including urology and others). Inverse probability treatment weighting (IPTW) was used to minimize potential baseline confounders. Cox proportional hazards models compared time to discontinuation between ARPIs. Results: Among 10,239 mCSPC patients initiating ARPI (Apa: n=2,340; Daro: n=889; Enza: n=7,010), 1,301 Apa, 625 Daro, and 4,708 Enza started in oncology settings; the remainder in non-oncology settings. After IPTW patient characteristics were well balanced. In oncology settings, Daro had the lowest discontinuation rate (53.0%) vs. Apa (62.8%) and Enza (66.2%) (p<0.0001). Median DOT was also longest in the Daro cohort (422 days [IQR: 180-1997]) vs Apa (369 days [IQR: 150-833]) and Enza (362 days [IQR: 150-811]). Daro had significantly lower risk of discontinuation compared to Apa (HR 0.87, 95% CI 0.8- 0.96) and Enza (HR 0.86, 95% CI 0.78- 0.94). In non-oncology settings, after IPTW (Apa: n=320; Daro: n=240; Enza: n=285), discontinuation rates were 50.7%, 58.8%, and 61.7%, respectively (p=0.024). Risk of discontinuation was not significantly different (Daro vs Apa: HR 0.91, 95% CI 0.8-1.02 and Daro vs Enza: HR 0.95, 95% CI 0.84-1.08). Conclusions: mCSPC patients treated with Daro in the oncology setting had significantly lower risk of discontinuation and longer treatment durations vs those receiving Apa or Enza. In non-oncology settings, Daro showed a numerically lower discontinuation rate, though time-to-discontinuation was not statistically significant, likely due to smaller sample sizes. Discontinuation rate by IPTW treatment cohort in the oncology setting. Daron=625 Apan=614 Enzan=653 p -value Median follow-up time (days) 479 550 490 Index drug discontinuation, n (%) 331 (53.0) 386 (62.8) 432 (66.2) <0.0001 3 month discontinuation, n (%) 91 (14.6) 114 (18.5) 105 (16.0) 0.163 6 month discontinuation, n (%) 158 (25.3) 191 (31.1) 196 (30.1) 0.0538 12 month discontinuation, n (%) 248 (39.7) 300 (48.8) 330 (50.6) 0.0002

Development and validation of computational histology artificial intelligence (CHAI)–powered prognostic and predictive biomarkers in metastatic hormone-sensitive prostate cancer (mHSPC) using ENZAMET and CHAARTED prospective randomized phase 3 trials (RCT).

231 Background: Advanced biomarkers (BM) for mHSPC are needed to improve personalized treatment. The CHAI platform applies deep learning to extract quantitative histologic features from H&E stained digitized whole slide images (WSI). Using two RCTs, we aimed to apply the platform to separately develop (dev) and externally validate (val) three distinct BMs in mHSPC: 1) a prognostic risk stratifier (ProgPC), and predictors for treatment benefit with 2) docetaxel (PredDoce), and 3) androgen-receptor pathway inhibitor (ARPI) (PredARPI). Methods: Dev and val used all cases with available H&E-stained diagnostic specimen WSI and clinical data from CHAARTED, ENZAMET, and a real world dataset (RWD) of mHSPC from an NCI Center (Table). For dev, the CHAI platform extracted quantitative histomorphologic features. Features associated with progression-free survival (PFS) & overall survival (OS) were selected to produce continuous scores which were then dichotomized into BM+ (benefit) and BM- (less benefit) categories. BMs and thresholds were optimized on the dev sets and locked. Each val used an independent held-out cohort to assess performance. Predictive performance was assessed via BM-treatment interaction in Cox-proportional hazards models. Results: 1179 pts were available: 507 CHAARTED; 584 ENZAMET; and 88 RWD. In val, for ProgPC, unfavorable pts had worse PFS & OS, even after controlling for clinical variables on multivariable analysis (MVA) (Table). For PredDoce, BM+ pts had superior PFS & OS, while BM- pts had no difference with the addition of docetaxel. For PredARPI, BM+ pts had superior PFS & OS, while BM- had less benefit with the addition of ARPI. For both predictive BMs, the BM-treatment interaction was significant for PFS & OS even when controlling for clinical predictors. Conclusions: We separately developed three distinct and clinically relevant BMs for mHSPC using a deep learning-based computational histology platform. All three externally validated for PFS and OS using two independent prospective phase 3 RCTs, and independently of clinicopathologic risk factors, demonstrating Simon's level IB evidence for biomarker validation. Clinical trial information: NCT00309985 ; NCT02446405 . Biomarker Dev Val Biomarker N (%) OS HR (95%CI) P Interaction P ProgPC CHAARTED ENZAMET Favorable 465 (80) Unfavorable 119 (20) 2.9 (2.2-3.8) <0.01* PredDoce ENZAMET(no enzalutamide arm) CHAARTED Benefit 260 (60) 0.60 (0.41-0.87) <0.01 0.02** Less benefit 163 (40) 1.03 (0.69-1.55) 0.8 PredARPI RWD + ENZAMET(15%) ENZAMET(85%) Benefit 224 (65) 0.5 (0.32-0.97) <0.01 0.01 Less benefit 121 (35) 1.22 (0.70-2.12) 0.5 *Control for age, ECOG, Gleason, PSA, treatment, volume (low/high), timing (metachronous/synchronous). **Control for volume*treatment, and timing*treatment interaction.

Precision diagnostics in prostate cancer treatment (PREDICT): A phase 2 multi-arm biomarker-based study (Alliance A032102).

TPS277 Background: Recent advances in genomic sequencing have deepened our understanding of the molecular complexity of metastatic castration-resistant prostate cancer (mCRPC), revealing multiple actionable alterations that now inform biomarker-driven treatment strategies. Accordingly, germline and somatic tumor profiling is recommended for all patients with mCRPC. Beyond DNA aberrations, gene expression profiling can uncover additional therapeutic targets and pathway activations. The phase 2 PREDICT trial is leveraging both DNA and RNA alterations to guide rationally designed, biomarker-based therapeutic approaches for patients with mCRPC. Methods: This multi-center, multi-arm, biomarker-driven phase 2 umbrella trial is evaluating rationally selected therapies for patients with metastatic castration-resistant prostate cancer (mCRPC). The primary endpoint is objective response rate in patients with measurable disease, with secondary endpoints including radiographic progression-free survival, PSA response, time to first symptomatic skeletal event, overall survival, safety, and correlative biomarker analyses. Eligible patients must have progressive mCRPC of any histology, prior treatment with an androgen receptor pathway inhibitor (ARPI), and either prior or declined taxane chemotherapy, with both measurable and non-measurable disease permitted. Enrollment requires standard-of-care next-generation DNA sequencing from tissue or circulating tumor DNA performed in a CLIA-certified laboratory, and RNA-based allocation will use the CLIA-certified Caris MI Tumor Seek assay (whole exome and whole transcriptome sequencing) on tissue obtained within 12 months of study entry, with a real-time molecular tumor board reviewing results to confirm arm assignment. Patients with RB1 loss (DNA), an RB functional loss signature (RNA), or an NEPC signature (RNA) will receive the EZH1/2 inhibitor valemetostat; those with ≥2 of 3 tumor suppressor gene alterations (TP53, RB1, PTEN), FANC alterations (DNA), or SLFN11 overexpression (RNA) will receive cabazitaxel plus carboplatin; and those without study-defined alterations will receive physician’s choice of cabazitaxel, ARPI, or 177Lu-PSMA-617. The design permits incorporation of additional biomarker-defined arms, and up to 158 patients per arm (64 with measurable and 94 with non-measurable disease) will be accrued under a Simon two-stage minimax design, providing a one-sided type I error of 0.05 if the true response rate is 0.20 and 90% power if the response rate is 0.37 (Clinical trial information: NCT06632977). Clinical trial information: NCT06632977 .

Detecting <i>FGFR3</i> genomicalterations in liquid biopsies from patients with clinically advanced urothelial bladder cancer.

830 Background: Fibroblast growth factor receptor 3 (FGFR3) pathogenic gain of function genomic alterations including activating short variant mutations, rearrangements/fusions and amplifications (FGFR2/FGFR3mut+) are associated with the development and progression of UBC and have emerged as major therapy targets for patients with clinically advanced urothelial bladder cancer (CAUBC). Erdafitinib is FDA-approved pan–FGFR inhibitor for metastatic UC harboring susceptible alterations in FGFR2/FGFR3 e.g. activating mutation or fusion. Conventional genomic testing for FGFR3 typically involves tumor tissue; however, circulating tumor DNA (ctDNA) can be a relevant biospecimen for such testing . We queried whether the tumor fraction (TF) calculation would impact the ability of FGFR3 GA to be detected on liquid biopsies (LBx). Methods: Hybrid capture based comprehensive genomic profiling (CGP) was performed on 10,531 CAUBC TBx using the FoundationOneCDx assay and on 1,637 CAUBC LBx using the FoundationOneLiquid CDx assay. The ctDNA tumor fraction (TF) for each LBx sample was determined using assessments of aneuploidy and variant allele frequencies, as previously described. Results: For the TBx group, 1,917 (18.2%) CAUBC were FGFR3 mut + . For the LBx group, FGFR3 mut+ detection was increased as the TF increased reaching a peak of 24.6% when the TF was ≥10% (Table). For CAUBC LBx samples with TF &lt; 1%, FGFR3 mut+ detection was 14.4%. As the LBx TF increased, the frequency of detection of FGFR3 mut+ increased reaching &gt; 24% when the TF was ≥ 30%. When the TF was ≥1.0% the frequency of FGFR3 mut+ was only slightly higher in LBx samples than TBx samples. Conclusions: LBx emerges as a sensitive method for detecting FGFR3 mut+ in CAUBC; but its sensitivity is dependent on TF. Importantly, LBx TF may play a major role in CGP evaluation, as FGFR3mut+ rates using LBx appear to be as frequently detected in LBx as in TBx samples, especially when the LBx TF is ≥1%. However, when TF levels are &lt; 1%, FGFR3 mut+ status may be missed, therefore FGFR3 testing cannot rely on LBx in such cases. Limitations include the retrospective nature, lack of clinical data annotation, possible selection, confounding biases, and lack of matched TBx and LBx samples. Our findings have the potential to increase LBx testing, especially in cases with insufficient tumor tissue available for CGP, and raise the question whether LBx may be complementary to TBx. CAUBC FGFR3 wt FGFR3 mut+ FGFR3 mut_freq TBx 8614 1917 18.2% LBx TF ≥0% 534 90 14.4% LBx TF ≥1.0% 254 68 21.1% LBx TF ≥5.0% 174 50 22.3% LBx TF ≥10.0% 132 43 24.6% LBx TF ≥20.0% 89 29 24.6% LBx TF ≥30.0% 63 19 23.2% LBx TF ≥40.0% 43 10 18.9% LBx TF ≥50.0% 32 7 17.9%

In Situ Copper‐Mediated Electron Bridge Revolutionizes Aqueous Sulfur‐Based Batteries

ABSTRACT The practical application of sulfur‐based batteries remains challenged by the sluggish charge transfer kinetics and structural instability of sulfur cathodes, largely attributed to the absence of efficient electron transport pathways and robust electrode architecture. Herein, we present an in situ electron bridge construction strategy by introducing a transition metal to tailor the electronic properties and reinforce the structure of sulfurized polyacrylonitrile (SPAN) cathode. The dynamic d‐p orbital hybridization between copper and SPAN within the electron bridge promotes bandgap closure, shifting the electronic character from a semiconducting state toward a metallic state, thereby establishing high‐speed electron transfer channels and accelerating redox kinetics. Simultaneously, the self‐assembled copper‐modified SPAN (CuSPAN), driven by in situ thermodynamically‐favorable process, intrinsically reinforces the cathode structure, conferring exceptional long‐term operational stability. As a result, the aqueous CuSPAN‐based battery achieves a high reversible capacity of 760 mAh g −1 at 3 C and outstanding cyclic stability with 79.2% capacity retention over 50 000 cycles at 15 C, superior to previously reported aqueous sulfur batteries. To verify the practicality, a flexible pouch cell is built based on the CuSPAN cathode, Zn anode, and gel electrolytes, delivering a stable operating voltage (1.2 V), high energy density (950 Wh kg −1 ), and remarkable cycling stability even under various harsh conditions.