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A phase II study evaluating the efficacy and safety of perioperative enfortumab vedotin plus toripalimab combined with endoscope-based kidney-sparing surgery for patients with high-risk upper tract urothelial carcinoma (WUTSUP-04-EV-JS001).

TPS905 Background: Radical nephroureterectomy (RNU) for high-risk upper tract urothelial carcinoma (UTUC) often compromises renal function and eligibility for adjuvant therapy, while kidney-sparing surgery (KSS) carries high recurrence risks. Given the efficacy of enfortumab vedotin (EV) plus PD-1 inhibitors in advanced disease, the phase II WUTSUP-04 trial investigates whether this combination can downstage high-risk UTUC, enabling successful KSS while preserving the kidney, as well as offering long-term disease control. Methods: Study Design and population: This is a prospective single-center phase II trial conducted at West China Hospital, Sichuan University (CTEC : 2025-763). Key eligibility criteria include adults with histologically confirmed, high-risk, non-metastatic UTUC (cTa-2N0M0) with tumor size ≤20 mm or deemed endoscopically resectable, and an imperative or relative indication for nephron preservation (e.g., solitary kidney, bilateral UTUC, chronic kidney disease, strong preference for KSS with informed consent). Additionally, a prospective collection of data from contemporaneous patients who underwent RNU by the same lead surgeon and met comparable eligibility criteria will be conducted to compare the long-term oncological outcomes between the two treatment strategies. The treatment regimen is delivered sequentially across distinct phases: In the induction phase, patients receive 3 cycles of systemic EV (1.25 mg/kg IV, Days 1 & 8) plus Toripalimab (240 mg IV, Day 1) every 3 weeks. After response assessment and subsequent local tumor ablation, patients enter the consolidation phase, which consists of 6 cycles of adjuvant EV plus Toripalimab, followed by Toripalimab monotherapy to complete one year of total therapy. Endpoints: The primary endpoint is conversion-free survival (CFS), defined as the time from inclusion to the date of RNU performed for any UTUC-related indication, or death. Secondary endpoints include clinical complete response rate after induction, disease-free survival, metastasis-free survival, overall survival, renal function preservation, and safety. Sample size: The study includes an initial safety run-in phase (n=6). A sample size of 55 participants (including safety run-in) is planned to estimate the 12-month CFS rate with a precision (95% CI width) of approximately 0.087, assuming an exponential survival model. The study is approved by the Clinical Trial Ethics Committee of West China Hospital, Sichuan University and is initiating patient recruitment. Clinical trial information: CTEC: 2025-763.

Molecular Polarity Attenuation Tailors Weak Solvation Structure with Accelerated Kinetics and Robust SEI for High‐Areal‐Capacity Large‐Format Pouch Zn‐Based Batteries

ABSTRACT Large‐format, high‐areal‐capacity aqueous Zn‐ion batteries are pivotal for practical energy storage but remain hindered by sluggish kinetics, heterogeneous local reactions, and drastic interfacial deformation. In this work, a molecular polarity‐weakening strategy of electrolyte additive is proposed to customize a rapid‐reaction‐kinetics solvation structure and a hybrid solid‐electrolyte interphase (SEI) for Zn metal pouch batteries. Leveraging this synergistic solvation‐SEI regulation, a 25 cm 2 Zn||Zn pouch symmetric cell achieves unprecedent 352 h stable cycling at 40 mAh cm −2 (DOD = 68%, 10 mA cm −2 ). More importantly, a 100 cm 2 Zn||I 2 pouch full battery delivers a high areal capacity of 9.8 mAh cm −2 and sustains nearly 400 h of stable cycling.

Flexible Hygroscopic Electronics for Real‐Time Moisture Sorption‐Desorption Monitoring and Smart Humidity Regulation

ABSTRACT Humidity regulation plays a critical role in precision electronics, advanced storage, thermal, and energy management applications. While real‐time monitoring of water molecule dynamics during moisture sorption and desorption processes could provide crucial hygroscopic parameters for smart humidity regulation, conventional gravimetric methods suffer from low tracking speed, limited accuracy, and an inability to perform in situ detection. Here, we report a flexible hygroscopic electronics (FHE) capable of simultaneously regulating environmental moisture and dynamically monitoring sorption‐desorption processes through water‐mediated resistive changes in confined space. The targeted electronics exhibit exceptional performance, including a fast hygroscopic response of ∼2.1 s at 90% RH, cycling stability, and stable sorption‐desorption properties over more than 50 cycles. By engineering a series of modular array‐based sensors, we achieve adjustable humidity control in enclosed spaces according to application‐specific requirements. As a proof‐of‐concept, the intelligent electronic array successfully maintains stable humidity conditions even in damaged equipment enclosures (>3.5 h) and provides rapid sensory alerts. This work establishes an intelligent core‐shell FHE system, that absorbs unexpected moisture through a bio‐based hygroscopic core and simultaneously monitors the water sorption/desorption behaviors by a thin conductive shell, which allows remote warning for potential seal risk of equipment in an early stage.

Reactive Carbide‐Based Synthesis and Microstructure of NASICON Sodium Metal All Solid‐State Electrolyte

Abstract Reactive carbide precursor‐based synthesis of NASICON‐type NZSP (Na 1+x Zr 2 Si x P 3‐x O 12 ) solid‐state electrolyte (SSE) is demonstrated, in contrast to the established oxide‐based approach. Exothermic decomposition of ZrC and SiC in air homogenizes microstructure, yielding 98% compact density after conventional sintering at 1200 °C. Quantitative stereology demonstrates that significant microstructural differences are present. Compacts of carbide‐derived Carb‐NZSP are 98% dense with a secondary zirconium oxide (ZrO 2 ) volume fraction of 0.2% ± 0.3%, versus 93% dense and 3% ± 1% for oxide‐derived baseline. For Carb‐NZSP, the secondary glassy phosphate phase is agglomerated, while for baseline, it is dispersed and percolated. Electrochemical testing combined with post‐mortem analysis demonstrates how microstructural control of secondary phases is critical for dendrite suppression: Carb‐NZSP critical current density (CCD) is 3.1 ± 0.8 mA cm − 2 at 0.1 mAh cm − 2 , versus 1.0 ± 0.7 mA cm −2 at 0.1 mAh cm −2 . Cryogenic focused ion beam (cryo‐FIB) analysis demonstrates that in both materials, the porous 2D sheet‐like sodium metal dendrites propagate around and subsume NZSP grains, likely following a path enriched with glassy phase and with porosity. Dendrites also flow around isolated zirconia particles. Phase field simulation reveals deflection of dendrites by mechanically tough zirconia, while brittle glassy phase accelerates dendrite growth, especially when finely distributed.

Prognostic significance of depressive symptoms in men with advance prostate cancer (PC): Results from the IRONMAN registry.

139 Background: Depression is common in advanced PC and impacts quality of life. Whether depressive symptoms directly influence survival or serve as markers of disease progression remains unclear. We leveraged IRONMAN (International Registry of Men with Advanced Prostate Cancer) to examine how self-reported depressive symptoms at baseline and 6 months relate to survival in men with advanced PC. Methods: Eligible patients included those with newly diagnosed metastatic hormone sensitive (mHSPC) or castration resistant PC with (mCRPC) or without metastases (nmCRPC) (n=3378, 2017-2024) with baseline EORTC QLQ-C30 and EPIC-26 questionnaires. Patients were classified as “depressed” if a patient scored ≥3 on “Do you feel depressed?” on EORTC and ≥3 on “How big a problem ...feeling depressed?” on EPIC-26. The primary outcome was overall survival (OS) from study enrollment to death, withdrawal, or last follow-up; secondary outcome was PC–specific survival (PCSS). Average OS was estimated using restricted mean survival time (RMST), the association between changes in depressive symptoms and survival outcomes was assessed using Cox and Fine–Gray models. Results: At enrollment, 11% reported depressive symptoms (mHSPC 12%, mCRPC 10%, and nmCRPC 8%). Compared with non-depressed, depressed patients were younger (67 vs 70 years), more smokers (16% vs 9%), more often from Europe/Africa (47%/14% vs 38%/11%), had higher baseline PSA (197 vs 82 ng/ml) and more antidepressant use (14% vs 8%, p<0.001). Baseline depression predicted worse OS (HR 1.46, 95%CI 1.15–1.86). The risk of PC-specific death was increased by 34% (HR 1.34, 95%CI 1.01–1.78) in depressed patients. RMST was 3.5 years for depressed vs 3.8 years for non-depressed patients. Among mHSPC patients, RMST was 3.5 vs 5.1 years respectively, and among mCRPC, 2.9 vs 3.2 years. At 6 months (n=2295), 88% never experienced depression, 5% had resolved depression, 4% developed new depression, and 3% had persistent depression. New-onset self-reported depression was associated with worse OS (HR 2.13, 95%CI 1.52–2.97), with RMST of 2.6 vs 3.6 years in never depressed patients. Persistent depression trended toward worse OS (HR 1.31, 95%CI 0.86–1.99), while resolved depression was not associated with worse OS compared to non-depressed patients (HR 1.03, 95%CI 0.68–1.55). PSA rise (≥25% and 2ng/ml from baseline) occurred in 4.4% of never depressed, 1.2% of resolved, 9.1% of new, and 9.2% of persistent depression patients (p=0.024) and was associated with worse OS (HR 4.97, 95%CI 3.65-6.77) at 6 months. Conclusions: Self-reported depressive symptoms were common among men with advanced PC and were strongly linked to patient outcomes, highlighting the need for routine screening and early intervention in advanced PC care. Future research is needed to determine whether interventions to address mental health challenges could lead to improved PC outcomes.

Early-onset prostate cancer: A time series analysis of age-stratified trends.

354 Background: Prostate cancer (PC) epidemiology has undergone substantial transformation over the past three decades, influenced in part by the evolving USPSTF screening recommendations. We aim to characterize these temporal trends in PC incidence and mortality across age strata using Surveillance, Epidemiology, and End Results (SEER) and the Global Burden of Disease (GBD) databases. Methods: SEER provides case-reported, population-based cancer data covering 45.9% of the U.S. population, while GBD provides modeled estimates representing 100% national coverage. Using SEER from 1975 to 2022, age-standardized incidence rates (ASIR) and mortality rates (ASMR) per 100,000 were extracted with age, race, and stage stratification (Historic Stage A data; 1992–2019). Complementary GBD data for the U.S. were analyzed for age-specific incidence (ASpIR), mortality (ASpMR) and disability-adjusted life years (DALYs) (1990–2022). Results: In SEER, ASIR of PC increased sharply among young men (<55 years), peaking between 2000 and 2009 before declining by 2020–2022. Among men aged 45–49 years, ASIR increased from 5.6 (1975–1979) to 42 (2000–2009) before falling to 22 by 2020–2022. Among the 50–54 age group, ASIR rose from 24 to 148 and then declined to 102 over the same timeframe. Conversely, ASIR among men aged ≥70 years declined markedly after the 1990s peak (from 1,137 to 476 in ages 85–89). Localized-stage ASIR in men aged 50–54 years rose from 70 (1990–1999) to 133 (2000–2009), then fell to 63 (2010–2019), while distant-stage ASIR increased modestly from 2.7 to 4.0 before dropping subsequently. Black men aged 50–54 years exhibited a more pronounced growth in ASIR (from 50 to 234) than White men (24 to 91) with PC. Despite these shifts, ASMR for men aged 50–54 remained stable (4.7 in 1975–1979 vs. 4.9 in 2020–2022). GBD data echoed these trends, showing a 70% rise in ASpIR among men 20–54 (10 to 17) and a 17% decrease among men ≥55 (808 to 587) from 1990–2022. ASpMR decreased in older men (−43%) and remained stable in younger cohorts (−2%) over the same timeframe. DALYs showed similar age-related divergence (Table 1). Conclusions: PC incidence in younger men in the U.S. peaked in the early 2000s and declined thereafter, coinciding with the USPSTF’s 2012 recommendation against routine PSA screening and subsequent revisions in 2018. SEER data revealed persistent racial disparities among black young men with PC. Overall, PC incidence has increased markedly in men under 55 years over the past five decades, while it has declined substantially in older age groups. This epidemiological shift toward younger onset disease, warrants investigation into emerging risk factors and screening recommendations. Age stratified trends in prostate cancer in the US, 1990–2022 (GBD). GBD 20-54 (1990– 2022; % change) 55+ (1990– 2022; % change) ASpIR 10–17, 70% 808–587, -27% ASpMR 0.64–0.63, -2% 163–94, -43% DALY 33–37, -12% 3319–1879, -43%

Prevalence and clinical impact of actionable genomic alterations in non–clear cell renal cell carcinoma: A review of NGS-based trials and real-world data.

556 Background: Non–clear cell renal cell carcinoma (nccRCC) comprises biologically diverse subtypes with limited evidence guiding systemic therapy. The role of next-generation sequencing (NGS) in identifying actionable targets and informing precision-based approaches remains incompletely defined. This study summarizes prospective and retrospective data on the prevalence of targetable genomic alterations and the clinical impact of molecularly guided treatment strategies in nccRCC. Methods: A structured review of phase II–III trials and translational datasets incorporating NGS or molecular profiling in nccRCC (papillary, chromophobe, translocation, FH-deficient, and SDH-deficient subtypes) was performed. Studies were included if they reported (1) the prevalence of actionable alterations or (2) outcomes associated with targeted therapy. Results: Across nine studies (≈1,100 evaluable patients), actionable genomic alterations were identified in ~25–40% of nccRCC cases, with marked variability by subtype. Papillary RCC commonly demonstrated MET activation (mutation, amplification, or chromosome 7 gain) in ≈40%, with treatment responses mainly in MET-driven tumors. In PAPMET/SWOG-1500, cabozantinib was superior to sunitinib irrespective of MET status, underscoring the need for integrated molecular selection. FH-deficient RCC was almost uniformly associated with germline FH mutations; in the phase II study by Srinivasan et al., bevacizumab plus erlotinib achieved an objective response rate (ORR) of 64–72% and median PFS > 20 months. Chromophobe RCC frequently harbored mTOR-pathway alterations (TSC1/2, MTOR) in 20–25%, with reported responses to everolimus. Translocation RCC, driven by TFE3/TFEB fusions (~5% of RCC), demonstrated the best outcomes with immune checkpoint inhibitor (ICI)–TKI combinations. SDH-deficient RCC typically involved germline SDH mutations (most commonly SDHB); though evidence remains limited, overlap with the VHL pathway supports the rationale for TKI therapy. Conclusions: Actionable genomic alterations occur in approximately one-third of nccRCC, most frequently involving MET and mTOR pathways. Comprehensive NGS testing should be considered across all non–clear cell subtypes to identify MET-, FH-, mTOR-, and SDH-driven disease, refine targeted therapy selection, and enable biomarker-driven clinical trial enrollment.

Olfactory receptor activation overcomes obesity

Universal Fluorine‐Free Proton Exchange Polymers for High‐Performance and Durable Fuel Cells Operable Under Severe Conditions

ABSTRACT Fluorine‐free proton exchange membranes (PEMs) could offer a promising alternative to perfluorosulfonic acid (PFSA) membranes, addressing challenges such as negative environmental impact, high cost, and limited performance under harsh conditions. However, fluorine‐free PEMs inherently suffer from low proton conductivity due to weaker acidity and poorly developed hydrophilic/hydrophobic phase‐separation, along with limited mechanical and chemical stability. Here, we report a novel and universal fluorine‐free PEMs featuring aliphatic chains in the backbone, which for the first time to dissolve all the issues mentioned, such as 2.6 times higher proton conductivity than PFSAs. Further physical reinforcement (SP‐PAC12 67 ‐QP‐4.5‐PE‐7) effectively extended their lifetime to 335.1 times of the original SP‐PAC12 67 ‐QP‐3.5, and exceeded 1.3 times of the state‐of‐the‐art fluorinated Nafion XL reinforced membrane, in the severely accelerated durability test. Furthermore, the fluorine‐free PEMs exhibited outstanding performance than Nafion XL, especially at elevated temperatures, proving their practical applicability as a promising alternative to the fluorinated counterparts.

Safety profile of darolutamide + ADT compared to enzalutamide, apalutamide, and abiraterone in metastatic castration-sensitive prostate cancer: Results from the first safety matching-adjusted indirect comparison.

137 Background: Indirect treatment comparisons in metastatic castration-sensitive prostate cancer (mCSPC) have predominantly focused on efficacy endpoints, with limited evaluation of safety outcomes or consideration of baseline imbalances. This analysis is the first matching-adjusted indirect comparison (MAIC) to evaluate the safety profile of darolutamide (DAR)+ADT versus other androgen receptor pathway inhibitors (ARPIs) in mCSPC. Methods: A MAIC was conducted using individual patient data from ARANOTE (DAR+ADT vs ADT) (n=600) and published aggregate data from ARCHES (enzalutamide (ENZ)+ADT), TITAN (apalutamide (APA)+ADT), and LATITUDE (abiraterone acetate + prednisone (ABI)+ADT). Rates of adverse events (AEs) of special interest in ARANOTE were compared between studies after adjusting for baseline differences in age, Eastern Cooperative Oncology Group performance status (0 vs. 1+), Gleason score (<8 vs. 8+), disease volume, timing of metastatic disease and presence of visceral metastases. Overall survival was used as an offset to account for varying study follow-up across trials. Results: DAR+ADT showed significantly lower rates of fatigue versus ENZ+ADT (RR 0.38, 95% CI 0.21–0.68; p=0.0011) and APA+ADT (RR 0.48, 95% CI 0.27–0.85; p=0.012), and significantly lower rash rates versus APA+ADT (RR 0.27, 95% CI 0.11–0.67; p=0.0043). Numerical trends favored DAR+ADT versus ENZ+ADT and ABI+ADT for hypertension and fractures. Falls and vasodilation/hot flush rates were similar, while mental impairment favored DAR+ADT versus ENZ+ADT (RR 0.60, 95% CI 0.10–3.49; p=0.57) (Table 1). Conclusions: In this first safety MAIC in mCSPC, DAR + ADT demonstrated a favorable safety profile compared with other ARPIs. Significant reductions in fatigue and rash, together with numerically lower rates of other adverse events, support the tolerability and differentiated safety profile of DAR + ADT. Clinical trial information: NCT04736199 , NCT02677896 , NCT02489318 , NCT01715285 . Rate ratios of AEs of special interest for DAR + ADT versus other ARPIs in mCSPC. AEs RR vs Enzalutamide + ADT (ESS=458.77) RR vs Apalutamide + ADT (ESS=540.41) RR vs Abiraterone acetate + ADT (ESS=245.25) Fatigue 0.38 (0.21, 0.68) (p: 0.0011) 0.48 (0.27, 0.85) (p: 0.012) 0.78 (0.35, 1.73) (p: 0.55) Fractures 0.52 (0.18, 1.54) (p: 0.24) 0.46 (0.17, 1.27) (p: 0.13) 0.46 (0.13, 1.65) (p: 0.23) Falls 0.47 (0.085, 2.62) (p: 0.39) 1.06 (0.24, 4.65) (p: 0.94) NR Rash 0.56 (0.17, 1.83) (p: 0.34) 0.27 (0.11, 0.67) (p: 0.0043) NR Hypertension 0.54 (0.27, 1.08) (p: 0.083) 0.93 (0.50, 1.73) (p: 0.83) 0.51 (0.24, 1.09) (p: 0.084) Vasodilation/Hot flush 0.89 (0.47, 1.69) (p: 0.73) 0.81 (0.43, 1.51) (p: 0.50) 0.73 (0.28, 1.88) (p: 0.51) Mental impairment 0.60 (0.10, 3.49) (p: 0.57) NR NR RR <1.00 favor darolutamide + ADT. ADT: androgen deprivation therapy. ESS: effective sample size. RR: rate ratio. NR: not reported.

Prospective evaluation of sexual function over 5 years in patients with localized prostate cancer treated with carbon-ion radiotherapy.

355 Background: Curative treatment options for localized prostate cancer (PC) include surgery and radiation therapy; however, changes in sexual function (SF) after treatment often influence therapeutic decision-making. We conducted a prospective study to assess longitudinal changes in SF over a 5-year period in patients with localized PC treated with carbon-ion radiotherapy (CIRT) alone at our institution. Methods: From April 2010 to March 2015, a total of 263 patients with localized PC underwent CIRT without concomitant hormone therapy. SF was prospectively evaluated using the Expanded Prostate Cancer Index Composite (EPIC), a validated patient-reported outcome (PRO) instrument. EPIC questionnaires were administered at baseline (pre-treatment), and at 1 month, 3 months, 1 year, 2 years, and 5 years post-treatment. This analysis included 113 patients with complete datasets across all time points. Institutional review board approval was obtained (approval number: 693). Results: The median age of the cohort was 64.6 ± 7.0 years (range: 41–82), and the median PSA level was 5.34 ± 1.81 ng/mL (range: 0.55–10.09). Clinical stages were T1 in 45% and T2 in 55% of patients. Mean EPIC sexual function scores at baseline, 1 month, 3 months, 1 year, 2 years, and 5 years were 31.2, 20.8*, 26.7, 25.3, 25.2, and 21.4*, respectively. Corresponding mean sexual bother scores were 84.3, 87.2, 83.8, 76.2, 79.7, and 78.8, while sexual summary scores were 44.9, 41.5*, 44.1, 40.7*, 42.1, and 39.1* (*p < 0.05 vs. baseline). When stratified by baseline sexual summary score using the median value (44.9) as a cutoff, patients were classified into a Good SF group (≥44.9) and a Poor SF group (<44.9). The Good SF group demonstrated a significant decline similar to the overall cohort, whereas the Poor SF group showed stable scores without notable deterioration over time. Conclusions: This prospective 5-year study delineated the trajectory of SF following CIRT for localized PC. Baseline SF status appeared to shape subsequent changes, suggesting that pretreatment sexual function may be an important determinant of long-term functional outcomes.

Blood and urine liquid biopsy for molecular monitoring in HER2-positive muscle-invasive bladder cancer under bladder-preserving therapy.

847 Background: While trimodal therapy is the current standard for organ preservation in muscle-invasive bladder cancer (MIBC), its clinical efficacy remains limited, and there is a critical need for noninvasive biomarkers to support real-time treatment decisions. This study explores a novel bladder-sparing approach combining immunotherapy-based neoadjuvant treatment with radiotherapy in patients with locally advanced MIBC. To enable dynamic monitoring of treatment response, a next-generation sequencing (NGS)-based liquid biopsy assay was utilized to assess molecular changes in both urine and blood. Methods: In this exploratory analysis, 29 patients from two Phase 2 trials (HOPE02, HOPE03) received neoadjuvant tislelizumab combined with gemcitabine plus cisplatin/carboplatin (HOPE02) or disitamab vedotin (HOPE03), followed by bladder-sparing radiotherapy based on treatment response. Tumor response was assessed via imaging and cystoscopic biopsy. Longitudinal blood and urine samples were collected at key time points for ctDNA and utDNA analysis using the PredicineCARE NGS assay to detect somatic alterations and monitor tumor fractions. Results: A total of 29 patients had eligible blood samples and 28 had eligible urine samples for molecular analysis, among whom 23 had paired blood and urine samples available from baseline. Urine samples yielded a higher number of somatic mutations compared to blood. At baseline, 276 mutations were detected in urine and 61 in blood, with 40 overlapping mutations identified across both sample types. The most frequently mutated genes in urine were TP53 (57%), TERT (43%), ARID1A (35%), KDM6A (35%), and RB1 (30%). In blood, the most prevalent mutations were observed in TP53 (39%), PIK3CA (13%), ARID1A (9%), ATM (9%), and BRCA2 (9%). At baseline, tumor fraction levels derived from the NGS assay in urine were significantly associated with pathological T stage (p = 0.0202) and HER2 expression levels determined by immunohistochemistry (p = 0.0263). In blood samples, TP53 mutations were significantly correlated with higher Ki67 expression (p = 0.0157) and larger baseline tumor size (p = 0.0108). Longitudinal assessment of tumor fraction dynamics identified five molecularly unresponsive patients via urine analysis and seven via blood analysis. Extended clinical follow-up is required to validate the association between these molecular findings and definitive clinical outcomes. Conclusions: Our study demonstrates the feasibility of a bladder-preserving strategy involving neoadjuvant immunotherapy combinations and radiotherapy in MIBC patients. NGS-based liquid biopsy using both urine and blood samples enabled dynamic monitoring of treatment response and showed strong correlations with clinical risk factors, underscoring its potential as a noninvasive tool to guide personalized therapy. Clinical trial information: ChiCTR2100045213.

The Biomarkers Consortium: 20 years of advancing precision medicine

Thermomechanics of Picoliter Liquids Encapsulated in Metal Microarchitectures

ABSTRACT Probing the mechanical behavior of liquids at the nanoscale—especially under hydrostatic stress with various strain rates and extreme temperature conditions—holds significant potential for advancing microfluidic, biomedical, and energy systems. However, it remains experimentally challenging due to the inherent difficulties in encapsulation of liquid at micro/nanoscale and in accurately applying and measuring stress within confined microscale environments. In this work, we present a novel single‐step method for liquid encapsulation at the microscale and subsequent in situ micromechanical testing at extreme dynamic thermomechanical conditions. Localized electrodeposition in the liquid process enables the direct formation of hollow copper microarchitectures containing picoliters of liquid. The presence of the encapsulated liquid was verified via structural analysis at cryogenic and elevated temperatures. We investigated the mechanical role of the confined liquid through compressive tests, demonstrating its incompressibility at room temperature and its enhanced load‐bearing capacity in the ice phase at −160°C. These results reveal enhanced energy dissipation due to the size‐dependent strength of ice. Additionally, we evaluated the tensile response of copper‐ice composites at −160°C using microfabricated push‐to‐pull structures. Our findings outline a new pathway for encapsulation of liquids in metal microarchitectures that could aid and impact fields of microelectronics, pharmaceuticals, and energy storage.

Function‐Oriented Modular Molecular Design of a Chitin‐Derived Self‐Healable Binder for Promising Zinc Powder Anodes

ABSTRACT Replacing zinc foil with Zn micropowders (ZnMPs) enhances manufacturing compatibility for Zn‐metal batteries but imposes challenges like uncontrolled Zn deposition and accelerated structural degradation, typically resulting in a short cycle life of < 50 cycles. Herein, we synthesize a multifunctional bottle‐brush polycationic binder based on naturally abundant and mechanically robust chitin, which enables exceptional long‐term Zn plating/stripping reversibility, averaging 99.5% Coulombic efficiency over 300 cycles. The design rationales are experimentally validated as follows: diverse functional groups integrated onto the chitin backbone provide multiple supramolecular interactions ensuring ZnMP electrodes’ spatial uniformity and structural robustness; Zn 2+ ‐carboxylate coordination simultaneously enhances the binder's mechanical strength (~1.2 MPa), toughness (~8.6 MJ m −3 ) and ionic conductivity (an 87% increase, reaching 1.72 × 10 −5 S cm − 1 ) upon swelling; while synergistic dynamic electrostatic interactions and hydrogen bonding permit rapid self‐recovery of the electrodes during cycling. This work underscores the promise of supramolecular engineering for binders targeting aggressive electrode chemistries.

ETCTN 10483: Phase Ib trial of erdafitinib (E) combined with enfortumab vedotin (EV) following prior therapies for metastatic urothelial carcinoma (mUC) with FGFR3/2 genetic alterations (GAs).

770 Background: Erdafitinib (E), a pan-FGFR inhibitor, is approved for FGFR3-altered mUC after prior therapy. Enfortumab Vedotin (EV) is active as monotherapy post-platinum and in combination with pembrolizumab (EVP) as 1 st line therapy in mUC. Retrospective studies suggest EV activity is maintained in FGFR 3/2-altered disease. Since EV and E have different mechanisms of activity and toxicities are mostly non-overlapping, we evaluated the feasibility, safety, pharmacokinetics (PK), and antitumor activity of E+EV in this population. Methods: Single arm, multicenter Phase Ib with 3+3 dose-escalation and expansion study of E at 8 mg daily orally + EV on days 1,8, and 15 every 4 weeks in FGFR3/2 altered mUC patients who progressed on prior therapies. EV dose level 1 (DL1) was 1 mg/kg, escalation dose was 1.25 mg/kg (DL2), and reduction was allowed to 0.75 mg/kg (DL -1). Primary objective: determine maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of EV with fixed dose of E. Secondary objectives: objective response rate, duration of response (DoR), progression-free survival (PFS), overall survival (OS), and PK. Results: Fifteen patients were enrolled and completed the dose limiting toxicity (DLT) period (1st cycle). Median age was 69 years and 13 (87%) were male. In dose-escalation, 6 patients were enrolled at DL1 with 1 DLT (skin rash) and 3 at DL2 (no DLT). The MTD and RP2D of EV was 1.25 mg/kg with E at 8 mg/day; an additional 6 patients were treated at RP2D. Common all-grade treatment-related adverse events (TRAEs) included hyperphosphatemia, AST increase, mucositis, diarrhea, fatigue, peripheral neuropathy, dry mouth, palmar–plantar erythrodysesthesia (PPE) and hypercalcemia. Grade 3–4 TRAEs were UTI 27%, PPE 20%, anemia 13%, lymphopenia 13%, vomiting 13%, Stevens–Johnson syndrome 7%, and hyponatremia 7%; there were no grade 5 events. PK: E Ctrough 1320±421 ng/mL. For the EV payload (MMAE), exposures aligned with monotherapy references—DL1: Ctrough 0.6±0.3, Cmax 3.9±0.9 ng/mL; DL2: Ctrough 0.9±0.6, Cmax 5.5±2.3 ng/mL. Objective responses were observed in 14 of 15 patients (93.3%, 95% CI: 68.1-99.8%), including 12 partial responses, 2 complete responses, and 1 stable disease. The median OS was 26.4 months (95% CI 12.1-NR); median PFS was 11.1 months (95% CI: 7.6-NR) with median follow up of 27.2 months (95% CI 18.6- NR). The median DOR was 8.25 months (range 1.7-24.2) among responders. Conclusions: E+EV was feasible, tolerable, and showed high anti-tumor activity in FGFR3/2-altered mUC. The magnitude of response in this small cohort supports a biologic rationale for dual targeting of FGFR3 signaling and NECTIN-4–mediated antibody drug conjugate with further prospective evaluation of EVP and FGFR3-selective inhibitors in larger biomarker-defined studies. Clinical trial information: NCT04963153 .

Characterization of HER2 expression in prostate cancer compared with other solid tumors.

255 Background: Recent reports of promising responses to the human epidermal growth factor receptor 2 (HER2)-targeting antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) in patients with HER2-expressing prostate cancer (PCa) (PMID: 39496182, 40638235) have prompted a clinical trial (CaRPET; NCT06610825) to evaluate T-DXd for the treatment of HER2-expressing metastatic castration-resistant PCa. HER2 expression by immunohistochemistry (IHC) is commonly observed in PCa in the absence of HER2 gene amplification, but reported rates vary due to inconsistent scoring. To address these challenges and better define the HER2 landscape in PCa, we performed a multi-platform analysis of HER2 expression using IHC, quantitative RT-PCR (qRT-PCR), and RNA-based transcriptional profiling (qTP) across a cohort of prostate tumors. We also compared the distribution of HER2 expression in PCa to that of tumors known to respond to HER2-targeted therapy to better understand its therapeutic potential. Methods: A cohort of 51 patients with PCa were selected and representative sections of formalin-fixed paraffin-embedded tissue from core biopsies and radical prostatectomies were blindly assessed for HER2 protein and mRNA expression using IHC and qRT-PCR, respectively. Normalized HER2 mRNA expression stratified by IHC scores was compared to a cohort of non- HER2 amplified breast cancer (BCa). Tumor-type distributions of HER2 RNA expression in non-amplified HER2 -expressing tumors from the Strata Select v4 pan-cancer dataset (n=12,155 tumors, 37 types) were analyzed. Results: qRT-PCR was performed for 51 patients (84% self-identified Black, 73% locally advanced, 20% metastatic) previously evaluated by HER2 IHC (IHC 0, 1+, 2+, 3+; n = 7, 20, 18, 6). The distribution of HER2 mRNA expression in PCa with IHC 0+ and IHC 1-3+ was most similar to that of BCa IHC 1+ and IHC 2+ respectively by Kolmogorov–Smirnov testing. In the Strata Select v4 cohort, PCa had the fifth highest median HER2 mRNA expression, between BCa (3rd) and non-small cell lung cancer (NSCLC) (7th), overall most resembling NSCLC (Jensen-Shannon Divergence 0.016). Conclusions: PCa exhibits HER2 expression by IHC, qRT-PCR, and qTP comparable to other tumors known to be responsive to anti-HER2 therapy. Integration of predictive biomarkers for ADC response with data from the CaRPET trial will help better understand the treatment response to HER2-targeting ADCs in PCa.

Comprehensive multi-layered omics analysis of the UBC landscape for precision medicine and its clinical implications: From deciphering distinct molecular heterogeneity to guiding treatment decision-making and developing tailored therapeutic strategies.

840 Background: Conventional transcriptomic subtyping of non-muscle invasive (NMIBC) and muscle-invasive bladder cancer (MIBC) fails to capture the complex molecular heterogeneity of urothelial bladder cancer (UBC). Our goal is to apply high-resolution multi-omics profiling to optimize risk stratification and management, and to elucidate novel biomarkers and therapeutic targets. Methods: Comprehensive multi-omics analyses were performed on 212 fresh frozen tumor tissues from 168 UBC patients (130 NMIBC and 38 MIBC) who underwent surgery at the National Cancer Center between 2020 and 2023. Results: Overall, the median mRNA–protein correlation (q = 0.307) was lower than that in other cancer types. Given the discordance, we integrated RNA sequencing, global proteomics, and phosphoproteomics for unsupervised clustering with non-negative matrix factorization (NMF). We identified four multi-omic clusters (NMF1–4) that encompass both NMIBC and MIBC, reflecting diverse oncogenic pathways and interactions within the tumor microenvironment. A Sankey diagram revealed partial overlaps between multi-omics NMF clusters and conventional transcriptomic subtypes. Furthermore, the limited and unpredictable efficacy of intravesical BCG and FGFR3 inhibition underscores the need for novel biomarkers and co-targets via a multi-omics approach. Genomic alteration analysis revealed that FGFR3 showed the strongest cis-effects, elevating both mRNA and protein levels. At the trans-acting level, FGFR3 alterations were linked to enhanced glycolytic processes. Proteogenomic analysis revealed FGFR3-mutant tumors enriched in extracellular matrix (ECM) and glycoprotein pathways with suppressed immune-regulatory programs. RNA-seq deconvolution and integrated transcriptomic–proteomic analyses revealed ECM remodeling, cancer-associated fibroblast (CAF) signatures, and the ECM modulator PLOD1 upregulation with reduced CD8⁺ T-cell infiltration in BCG non-responders. A strong correlation between PLOD1 ex-pression and CAF abundance in BCG non-responders, along with elevated SPP1 phosphorylation in the CAF(high)/PLOD1(high) subset suggests that disrupting the CAF–PLOD1–SPP1 circuit alongside BCG treatment may effectively address BCG failure, based on a novel framework linking CAF activation, ECM remodeling, and phospho-signaling dynamics. Conclusions: Our integrative multi-omics approach identified clinically relevant clusters that stratify all stages of UBC and bridged genomic–transcriptomic heterogeneity to actionable protein targets for precision oncology. Future efforts should focus on translating these findings into clinical applications while overcoming widespread adoption challenges.

Hunting for biopharma’s innovation sweet spot

Bulk‐to‐IHP Zn Interphase Engineering With Mannitol Additive Enables (002)‐Textured Zn Plating With Suppressed Hydrogen Evolution Reaction for Ah‐Level Aqueous Zinc‐Iodine Pouch Cells

ABSTRACT Aqueous zinc‐iodine batteries are promising contenders for next‐generation grid‐scale energy storage batteries. However, their deployment is hindered by zinc anode degradation at moderate cycling rates (0.5–2 C), including dendrite growth and parasitic hydrogen evolution reaction (HER), stemming from an unstable Zn/electrolyte interphase. Herein, a sugar alcohol‐based multifunctional additive of mannitol (ML), identified via theoretical screening based on molecular characteristics of electrostatic polarity, H 2 O binding energy, and LUMO level, is proposed to achieve comprehensive Zn/electrolyte interphase stabilization from the bulk phase to the inner Helmholtz plane (IHP). Leveraging abundant hydroxyl groups and good Zn 2+ affinity, ML disrupts the bulk hydrogen‐bond network and reconstructs Zn 2+ solvation structure, simultaneously suppressing proton‐hopping pathways and accelerating Zn 2+ desolvation. Moreover, robust chemisorption of ML molecules on both Zn (002) and Zn (101) planes modulates Zn deposition toward the thermodynamically stable (002) texture with enlarged grain size, thereby enabling dendrite‐free plating. Benefiting from these synergistic effects, Zn||I 2 full cells achieve an ultrahigh areal capacity of 6.5 mAh cm −2 over 3000 cycles at a practical rate of 1 C. Multiple Ah‐level Zn||I 2 pouch cells are also demonstrated, sustaining 1000 cycles with only 0.02% capacity decay per cycle, underscoring strong prospects for practical large‐scale application.