Browse Articles

Health-related quality of life, pain, and symptomatic skeletal events in the phase 3 PSMAddition study of [ ¹⁷⁷ Lu]Lu-PSMA-617 ( ¹⁷⁷ Lu-PSMA-617) combined with ADT and ARPI in patients with PSMA-positive mHSPC.

18 Background: In PSMAddition (NCT04720157), combining 177 Lu-PSMA-617 with ADT + ARPI significantly improved rPFS, vs ADT + ARPI, in patients with PSMA+ mHSPC (HR 0.72; 95% CI 0.58, 0.90; p = 0.002) at interim analysis 2 (IA2). We present health-related quality of life (HRQoL), pain and symptomatic skeletal events (SSE) results at rPFS IA2 (data cutoff, Jan 13, 2025). Methods: Eligible patients had treatment-naive/minimally treated (≤45 days pre-consent) mHSPC and ≥1 PSMA+ metastatic lesion on [ 68 Ga]Ga-PSMA-11 PET/CT. Patients were randomized 1:1 to 177 Lu-PSMA-617 (7.4 GBq ± 10% q6w, 6 cycles) + ADT + ARPI ( 177 Lu-PSMA-617 arm) or to ADT + ARPI alone (control arm). The primary endpoint was rPFS (BIRC-confirmed rPD by PCWG3/RECIST v1.1 or death). Safety and tolerability were secondary endpoints. Secondary endpoints also included time to worsening (TTW) in patient-reported HRQoL (FACT-P, EQ-5D-5L) and pain (BPI-SF), defined as composites of score worsening by prespecified thresholds, clinical progression, or death; and composite time to SSE (TTSSE) or death. Post hoc non-composite analyses excluded death and clinical progression. Results: 1144 patients were randomized. Median study treatment exposure was 20.6 months in the 177 Lu-PSMA-617 arm and 19.94 months in the control arm. Overall incidences of grade ≥3 AEs and serious AEs were 50.7% and 26.6%, respectively, in the 177 Lu-PSMA-617 arm and 43.0% and 22.8% in the control arm. HRs for TTW in all FACT-P, EQ-5D-5L, and BPI-SF scales/subscales were >1.0 but <1.2, and all 95% CIs included 1.0 (Table) ( 177 Lu-PSMA-617 arm vs control arm). Post hoc results were similar. The HR for TTSSE was 0.89 (95% CI 0.62, 1.26); medians were not reached. Post hoc results were similar. Conclusions: Combining 177 Lu-PSMA-617 with ADT + ARPI improved rPFS, with a trend toward prolonged TTSSE, vs ADT + ARPI, in patients with PSMA+ mHSPC. The frequency of AEs was slightly increased, but there were no clinically significant differences in TTW in HRQoL and pain. Clinical trial information: NCT04720157 . Pre-specified composite TTW, months – median (95% CI) 177 Lu-PSMA-617 arm (n = 572) Control arm (n = 572) HR (95% CI) FACT-P  Total score 11.33 (8.84, 14.03) 17.12 (13.80, 19.91) 1.14 (0.98, 1.33)  Physical well-being 9.20 (7.72, 11.79) 14.49 (11.47, 19.35) 1.16 (0.99, 1.35)  Emotional well-being 22.67 (17.08, 27.89) 23.29 (20.04, 28.16) 1.05 (0.88, 1.24)  Functional well-being 8.80 (7.43, 11.47) 11.14 (8.31, 13.83) 1.01 (0.87, 1.17)  Social/family well-being 8.77 (7.39, 11.24) 11.50 (8.54, 16.46) 1.05 (0.91, 1.22) EQ-5D-5L  Utility score 11.10 (8.84, 14.06) 15.67 (11.76, 19.12) 1.13 (0.97, 1.31) BPI-SF  Pain intensity 11.53 (8.77, 14.09) 13.83 (11.10, 16.79) 1.02 (0.87, 1.18)  Pain interference 13.44 (11.33, 17.64) 17.45 (14.03, 23.75) 1.12 (0.95, 1.31)  Worst pain intensity 11.14 (8.57, 12.65) 11.99 (9.23, 16.36) 1.01 (0.87, 1.18)

Micro‐Terraced Surface Induced Directional Two‐Dimensional Diffusion Enables Dendrite‐Free Zinc Anodes

ABSTRACT Aqueous zinc batteries have garnered significant attention owing to their low cost, high intrinsic safety, and environmental friendliness. However, their practical application is still hindered by poor cycling stability, primarily caused by uncontrolled Zn dendrite growth. Conventional strategies to suppress dendrites generally aim to convert undesired 2D diffusion, which favors dendrite formation, into 3D diffusion to promote uniform Zn deposition. In contrast, this study reports a dendrite‐free Zn plating behavior achieved through directional 2D diffusion enabled by a micro‐terraced surface, which is achieved by a Ti 4+ ‐etching strategy. Unlike conventional 2D diffusion, where Zn atoms aggregate and form dendrites, on the micro‐terraced surface Zn atoms rapidly and orderly migrate along the terraces toward their intersection boundaries, resulting in uniform, dendrite‐free plating. The micro‐terraced Zn anodes deliver exceptional cycling stability over 6250 cycles at 5 mA cm −2 /1 mAh cm −2 . When paired with I 2 cathode, the full cells achieve above 83.4% capacity retention and average Coulombic efficiencies of 99.89% over 5000 cycles at 1.5 A g −1 . This work provides mechanistic insights into Zn deposition and offers a new design paradigm for developing high‐stability energy storage systems.

Low Efficiency Roll‐Off and High Current Efficiency Light‐Emitting Diode Enabled by Graded CdSe/ZnSe/ZnS Colloidal Quantum Wells

ABSTRACT Colloidal quantum well light‐emitting diodes (CQW‐LEDs) hold tremendous potential for next‐generation display and lighting applications, owing to their high color purity, excellent efficiency, and low fabrication cost. However, efficiency roll‐off at high current density makes it challenging to achieve high brightness and long lifetime. Here, we designed CdSe/ZnSe/ZnS core/shell/shell CQWs with near‐unity photoluminescence quantum yield. The graded heterostructure promotes carrier injection, and the bottom‐emission device based on CdSe/ZnSe/ZnS CQWs exhibits remarkably suppressed efficiency roll‐off with a record‐high J 90 (current density for EQE to decrease to 90%) of 485 mA/cm 2 and a long operational lifetime (T 95 @ 100 cd/m 2 ) over 47000 h. In addition, the top‐emission device also shows low efficiency roll‐off and high current efficiency of 36.5 cd/A. This study provides a compositionally graded approach to suppress efficiency roll‐off in CQW‐LEDs, demonstrating the strong potential of the newly developed CQWs for next‐generation ultrabright and highly efficient optoelectronic devices.

Identification, functional characterization, and structural analysis of an atypical l-threonate 3-dehydrogenase

FGFR-altered metastatic urothelial carcinoma in the real-world setting: Insight from the multicenter, prospective, non-interventional Italian registry of advanced/metastatic urothelial carcinoma (SATURNO)—A FICOG and Meet-URO study.

681 Background: The therapeutic landscape of metastatic Urothelial Carcinoma (mUC) is rapidly evolving, alongside increasing opportunities to analyze molecular alteration and molecular classification. FGFR alteration (FGFRa) occur in about 15-20% of mUC patients. Data from randomized-controlled THOR trial demonstrated the clinical efficacy of erdafitinib, an FGFR 1-4inhibitor, in pretreated FGFR3/2a mUC. So, real-world data (RWD) on FGFRa patients remain an unmet need. Methods: SATURNO (NCT06235268) is an Italian, multicenter, prospective, non-interventional study enrolling all mUC patients managed at the participant institutions from Nov 2023 to Sept 2025. The Web National Registry includes patients with metastatic disease or with nodal involvement not suitable to surgery. Participating institutions were selected to adequately represent different geographical area. Results: A total of 237 patients were tested for FGFRa. Among them, 171 (72%) were FGFR3/2a and 66 (28%) were FGFR wild-type (WT). In the FGFR3/2a group, 134/171 (78%) were male and 37/171 (22%) were female; 165/171 (96%) had pure urothelial carcinoma histology. The most common metastatic sites were lung (61/171, 35%), liver (21/171, 12%), bone (41/171, 24%), and retroperitoneal lymph nodes (50/171, 29%). Compared with FGFR WT patients, older age was significantly associated with FGFR3/2a (OR 1.05, 95% CI 1.02–1.09, p = 0.003). Retroperitoneal lymph node involvement was less frequent among FGFR3/2a patients (29% vs 44%, OR 0.53, 95% CI 0.29–0.95, p = 0.033). FGFR3/2a tended to be more common in upper tract urothelial carcinomas (UTUC) compared with bladder tumors (23.4% vs 12.1%, OR 2.12, 95% CI 0.98–5.15, p = 0.073). FGFR3/2a patients were less likely to receive maintenance therapy (OR 0.36, 95% CI 0.19–0.65, p < 0.001). Among patients treated with platinum-based combinations (91/171, 53%), 41/91 (45%) FGFR3a patients received avelumab maintenance compared to 31/58 (53%) in the FGFR WT subgroup. Additionally, 26/91 (29%) FGFR3a patients had primary refractory disease to platinum-based therapy, compared with 14/58 (24%) among FGFR WT patients. Conclusions: RWD from this prospective registry show that FGFR3/2a is more common in older patients and, consistent with previous reports, tends to occur more frequently in UTUC. Retroperitoneal nodal involvement, usually associated with better prognosis, is less common in FGFR3/2a. FGFR3/2a are less likely to receive avelumab maintenance therapy due to primary progression to platinum-based combination. Acknowledgments: The IT infrastructure on which the urothelial tumor registry is based was developed thanks to the unconditional support of Gilead Sciences. Clinical trial information: NCT06235268 .

Real-world utilization and timing of initiation of bone-targeting agents (BTAs) in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with radium-223: Results from Princess Margaret Cancer Centre (PM).

68 Background: Patients with metastatic castration-resistant prostate cancer (mCRPC) and bone metastases treated with Radium-223 are at high risk for skeletal-related events (SREs), which contribute substantially to morbidity and mortality. Bone-targeting agents (BTAs), including zoledronic acid (ZA) and denosumab (Dmab), are recommended by guidelines for SRE protection. We examined real-world utilization and timing of BTA initiation in this high-risk population at a high-volume academic center. Methods: We retrospectively reviewed 252 patients with mCRPC and bone metastases treated with Radium-223 at PM between 2015 and 2024. SREs were defined as spinal cord compression, pathological fracture, or bone metastases requiring radiotherapy or surgery. We assessed the timing of BTA initiation relative to SRE onset and Radium-223 initiation. Pre-planned multivariable analyses (MVA) adjusted for age, baseline PSA, ECOG performance status, and prior SRE history. Results: Radium-223 was administered to 252 patients for an average of 5 cycles. Median age was 73.8 years (39.6-93.4) and median PSA was 44.4 ng/mL (0.4-7238). All patients received prior hormonal therapy, 42.9% had prior Docetaxel; 56.3% had SREs before starting Radium-223. BTAs were prescribed in 153 patients (60.7%) for a median duration of 26.4 months (1.2-110.4). While 129 patients (51.2%) initiated BTAs before Radium-223, 54 (21.4%) started BTA therapy after experiencing an SRE BTAs used included ZA (19%), Dmab (38.9%), and both agents in 2.8%. BTA usage increased over time, from 43.3% in 2009-2015 to 71.6% in 2016-2024. After a median follow up of 14.9 months (0.2-81.5), SREs occurred in 177 patients (70.2%), and 129 (51.2%) experienced recurrent SREs despite BTA use. The rate of pathologic fractures was 23.2%. On MVA, prior SRE history (HR 6.83, 3.48-13.40, p < 0.001) was associated with an increased risk of recurrent SREs, while initiation of Dmab (HR 0.28, 0.13-0.62, p < 0.002) or ZA (HR 0.14, 0.06-0.36) p < 0.001) had an overall protective effect. Conclusions: In this real-world cohort at high risk for SREs, BTAs remained under-utilized and were frequently initiated after the onset of SREs, despite guideline recommendations for early SRE prevention. Although BTA utilization has improved over time, many patients continue to experience recurrent SREs despite BTA therapy. These data underscore the importance of earlier BTA initiation and highlight the need for strategies to further reduce SREs.

Effect of tryptophan–serotonin–kynurenine pathways on immune landscape and survival in clear cell renal cell carcinoma: TCGA-KIRC transcriptomic analysis.

542 Background: Tryptophan metabolism regulates immune tolerance via the kynurenine (IDO1, TDO2) and serotonin (TPH1, HTRfamily) pathways. Kynurenine accumulation drives T-cell exhaustion, whereas serotonin signaling may enhance immune activation. Recent data suggest selective serotonin reuptake inhibitors (SSRIs) can augment immune checkpoint inhibitor (ICI) efficacy, yet the molecular underpinnings remain unclear in clear-cell renal cell carcinoma (cRCC). Methods: RNA-seq data and clinical information for TCGA-KIRC (Kidney Renal Clear Cell Carcinoma, n = 537) were obtained from UCSC Xena. Gene-set enrichment analysis (ssGSEA) quantified kynurenine and serotonin pathway activity. RNA-seq expression and clinical data for TCGA-KIRC (n = 537) were analyzed using single-sample gene-set enrichment analysis (ssGSEA) to quantify kynurenine and serotonin pathway activity. Immune marker genes (TIGIT, CD8A, CXCL10, PDCD1, LAG3, CTLA4) were correlated with pathway scores using Spearman’s ρ. Associations with overall survival (OS) were evaluated via Cox proportional-hazards models and Kaplan–Meier analyses. Results: The kynurenine pathway showed strong positive correlations with multiple checkpoint markers (CD8A ρ=0.35, PDCD1 ρ=0.30, LAG3 ρ=0.30, TIGIT ρ=0.37; all FDR < 0.001), suggesting association with an immune-inflamed but exhausted microenvironment. Conversely, the serotonin pathway exhibited inverse correlations with key inhibitory receptors (PDCD1 ρ=-0.21, CTLA4 ρ=-0.24, LAG3 ρ=-0.25; all FDR < 0.01), implying an immune-activated yet less exhausted phenotype. In survival analyses, high serotonin-pathway activity was associated with significantly longer OS (HR 0.06, 95% CI 0.005–0.75, p=0.03), while the kynurenine pathway trended toward improved outcome (HR 0.16, 95% CI 0.02–1.11, p=0.06). Conclusions: Transcriptomic activation of the serotonin pathway was linked to reduced expression of immune checkpoint receptors and improved survival in cRCC, whereas kynurenine activity correlated with immune exhaustion markers. Together, these findings suggest serotonin metabolism may define an immune-favorable, checkpoint-low state, potentially explaining emerging clinical observations of enhanced ICI response among patients receiving SSRIs. Correlation of kynurenine and serotonin pathway activity with immune checkpoint markers and overall survival in TCGA-KIRC. Pathway Survival HR (%95 CI) Survival p-values TIGIT CD8A CXCL10 PDCD1 LAG3 CTLA4 Kynurenine 0.16(0.02–1.11) 0.06 0.37 0.35 0.32 0.3 0.3 0.27 Serotonin 0.16(0.02–1.11) 0.03 -0.16 -0.13 -0.11 -0.21 -0.25 -0.24

Efficacy and safety of darolutamide and ADT in patient subgroups by baseline comorbidities and concomitant medications: ARANOTE <i>post hoc</i> analyses.

178 Background: Darolutamide (DARO) + androgen deprivation therapy (ADT) significantly improved radiological progression-free survival (rPFS) vs placebo (PBO) + ADT (HR 0.54, 95% CI 0.41–0.71; P&lt;0.0001) in patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC) in the phase 3 ARANOTE (NCT04736199) trial, with a favorable safety profile. DARO is also associated with low blood-brain barrier penetration and limited drug-drug interactions. Here, we report outcomes in pts treated with DARO or PBO by comorbidities (comorbid) and use of concomitant medications (conmeds) at baseline (BL). Methods: Pts were randomized 2:1 to DARO 600 mg orally twice daily or PBO, both with ADT. Pts were grouped by median number and type of comorbid or conmeds reported at BL. A post hoc analysis was conducted for rPFS and hazard ratios (HR) were estimated using a Cox regression model. Descriptive statistics summarized BL demographics, disease characteristics, and treatment-emergent adverse events (TEAEs) by treatment group. Results: BL demographics and disease characteristics were generally similar between DARO (n=446) and PBO (n=223) across all subgroups, defined as a median of ≤4 or &gt;4 comorbid or conmeds. An rPFS benefit for DARO vs PBO was seen across all comorbid (≤4, HR 0.46, 95% CI 0.32–0.65; &gt;4, HR 0.58, 95% CI 0.36–0.93) and conmed (≤4, HR 0.48, 95% CI 0.32–0.72; &gt;4, HR 0.61, 95% CI 0.38–0.97) subgroups. When analyzing specific comorbidities reported at BL that are commonly associated with mHSPC and older age, DARO showed a consistent rPFS benefit compared with PBO, including in pts with/without metabolic (n=185/415), cardiovascular (n=372/228), renal or urinary (n=237/363), gastrointestinal (n=113/487), and musculoskeletal (n=190/410) disorders (HR range: 0.35–0.62). With DARO, the rPFS benefit was similar in pts with cardiovascular disorders with or without corresponding conmeds (HR 1.07, 95% CI 0.58–1.94) and in pts with metabolic disorders with or without corresponding conmeds (HR 0.83, 95% CI 0.42–1.64). TEAEs, including those commonly associated with androgen receptor inhibitors and ADT, were generally similar between DARO vs PBO across comorbid (grade 3–5; ≤4, 34.1% vs 32.8%; &gt;4, 38.4% vs 43.4%), and conmed subgroups (grade 3–5; ≤4, 33.5% vs 34.7%; &gt;4, 39.4% vs 48.6%). Discontinuations due to TEAEs in the DARO group were lower vs PBO for all pts in both the comorbid (≤4; 4.7% vs 6.3%; &gt;4, 8.0% vs 15.8%) and conmed (≤4; 3.3% vs 6.9%; &gt;4, 8.8% vs 16.2%) subgroups. Conclusions: Overall, DARO demonstrated rPFS efficacy, regardless of comorbid or conmeds reported at BL, including pts with cardiovascular or metabolic disorders, with or without corresponding conmeds. DARO was well tolerated across all subgroups, with no new safety signals, supporting the use of DARO in mHSPC, even in pts with substantial comorbidities and greater use of concomitant medication. Clinical trial information: NCT04736199 .

Intramolecular Hydrogen Bonds Enhanced Quinone‐Based Anode for High‐Performance Aqueous Proton Batteries

ABSTRACT Aqueous proton batteries (APBs), utilizing redox‐active organic materials as the minimal hydrate proton charge carriers, have emerged as promising candidates for next‐generation energy‐storage. However, conventional quinone‐based electrode inclines to suffer from critical limitations, including electrode dissolution and sluggish reaction kinetics in strong acid electrolytes. To overcome this challenge, a quinone‐based polymer (HMND) material with intermolecular hydrogen bonds (HBs) was designed as an anode for APBs. This material forms HBs (C═O⋯N─H) between O in ─C═O and H in ─NH 2 that can not only significantly enhance the cycling stability of the organic electrode but also endow it with outstanding rate capability by accelerating proton transfer through the Grotthuss mechanism. The proton insertion/extraction mechanism has been verified through DFT, in situ/ex situ Raman spectra, and FT‐IR. Furthermore, the full APBs coupled with MnO 2 @GF cathode delivers a long lifespan of 42 000 cycles with a capacity decay rate of only 0.0018% per cycle at 8 A g −1 , along with an excellent rate performance (212.5 mAh g −1 at 1 A g −1 , 91.4 mAh g −1 at 70 Ag −1 ). It consistently showcases outstanding electrochemical performances even under extreme conditions in a frozen electrolyte at −60 °C, implying great potential for energy storage applications under extreme temperature scenarios.

Sulfonate‐Mediated Cation‐Switching in Hydrogel Electrolytes to Unlock Fast Ion Transport for Low‐Temperature Zinc Batteries

ABSTRACT Hydrogel electrolytes (HEs) are promising for zinc batteries owing to their high safety and intrinsic flexibility. However, limited carrier transfer kinetics from bulk phase to the interface of HEs hinder their practical applications at low temperatures. Here, we proposed a sulfonate‐mediated cation‐switching strategy to design antifreezing HEs with rapid ion transport for Zn batteries. The introduced Li + replaces Zn 2+ from oxygen coordination sites via strong sulfonate (−SO 3 − ) binding within the polymer matrix. The Li + ‐O bonds contract the polymer network, which in turn squeezes and rearranges the water molecules and ions in the pores into a highly interconnected state. This shifts the ion transport from a hopping‐dominated transport to a diffusion‐controlled, enhancing both ionic conductivity (7.75 mS cm −1 ) and Zn 2+ transference number (0.32) at −40°C. The liberated Zn 2+ further coordinates free water, lowering the glass transition temperature to −53.5°C. Moreover, the sacrificial process of polymer and salts results in the gradient interphase with a ZnS/ZnCO 3 ‐rich surface and a Li 2 S/Li 2 CO 3 ‐rich bottom, which reduced the Zn 2+ ‐diffused activation energy by nearly 50%. The Zn||VO 2 ‐V 2 O 5 /NC full cell with optimized HEs cell exhibits 83.7% capacity retention (5 000 cycles, −40°C) and 92% retention at 180° bending.

The antiseizure medication stiripentol inhibits mitochondrial complex I by blocking early-stage electron transfer

Serum amyloid A4 and cognitive functioning in long-term testicular germ cell tumor survivors.

606 Background: Long-term cognitive impairment has been described in survivors of testicular germ cell tumors (GCT) following curative treatment. Serum Amyloid A4 (SAA4) is a constitutively expressed apolipoprotein involved in lipid transport and metabolism. Unlike other SAA family members, SAA4 is not markedly induced during acute inflammation but has been linked to chronic inflammation, suggesting a potential role in neuroinflammatory processes and cognitive decline. Elevated SAA levels have been associated with post-stroke cognitive impairment and neurodegenerative diseases; however, SAA4 has not previously been studied in GCT survivors. This study aimed to evaluate the association between plasma SAA4 levels and self-reported cognitive functioning in long-term GCT survivors. Methods: GCT survivors (N = 177) followed at the National Cancer Institute, Slovakia, completed the Functional Assessment of Cancer Therapy – Cognitive Function (FACT-Cog) questionnaire during annual follow-up. The median follow-up time was 9 years (range 4-32). Peripheral blood was obtained during the same visit, and plasma SAA4 concentrations were quantified by ultra-high performance liquid chromatography and mass spectrometry in selected reaction monitoring mode (UHPLC-SRM/MS). Cognitive outcomes were assessed across four domains and overall cognitive function score, dichotomized into high (better) and low (worse) groups by median split. Survivors were treated with orchiectomy and active surveillance (n=23), cisplatin-based chemotherapy (n=131), radiotherapy (n=14), or both chemotherapy and radiotherapy (n=9). Results: Survivors with lower overall cognitive function scores had higher SAA4 plasma levels compared with those with higher scores (mean ± SEM: 26.42 ± 1.24 mg/L vs. 21.94 ± 1.23 mg/L; p = 0.02). Similarly, higher SAA4 was observed in survivors with worse perceived cognitive impairment (26.13 ± 1.25 mg/L vs. 22.23 ± 1.24 mg/L; p = 0.03) and poorer quality of life affected by cognitive impairment (25.75 ± 1.26 mg/L vs. 22.64 ± 1.24 mg/L; p = 0.056). No statistically significant differences in SAA4 plasma levels were found across treatment groups, which may be partly due to small subgroup sizes. Conclusions: Higher plasma SAA4 levels were associated with worse cognitive functioning in long-term GCT survivors. To our knowledge, this is the first study to evaluate SAA4 in this population. The findings suggest that chronic inflammation and altered lipid metabolism may contribute to cognitive impairment after cancer treatment. SAA4 and related apolipoproteins warrant further investigation as potential biomarkers of cancer-related cognitive impairment and other long-term treatment toxicities in GCT survivors.

Tumor microenvironmental NRG1 activation of HER3 as a driver of resistance to PI3K pathway inhibition in prostate cancer.

263 Background: Despite the prevalence of phosphoinositide 3-kinase (PI3K) pathway alterations in prostate cancer (PCa), the clinical efficacy of PI3K-targeted therapies in combination with androgen deprivation therapy (ADT) has been limited. The dichotomy between effectiveness in cancer cell lines and lack of effectiveness in patient tumors led us to hypothesize that the tumor microenvironment (TME) may play an important role in driving drug resistance in PCa. In this study, we designed a comprehensive secreted factor screen to determine novel TME-mediated resistance mechanisms to PI3K pathway inhibitors in PCa. Methods: A curated library of 297 secreted factors was screened for their effects on drug response in LNCaP, 22Rv1, VCaP, C42B, and PC3 prostate cancer cell lines. Cells were treated with PI3K pathway inhibitors (GDC-0941, Capivasertib, Sapanisertib) alone and in combination with enzalutamide, an androgen receptor inhibitor. The expression of secreted factors was assessed in human prostate tumors using immunohistochemistry from The Human Protein Atlas. Mechanistic validation was performed using western blotting and viability assays with siRNA and targeted antibodies. In vivo efficacy was tested in cell line-derived xenograft models. Results: Primary screening identified Neuregulin 1 (NRG1) as a top secreted factor that conferred resistance to PI3K inhibitors. NRG1 was found to be expressed in 10/12 (83%) of prostate cancer tumors, in the stromal cell compartments. Cell viability assays demonstrated that NRG1 treatment leads to resistance to multiple PI3K pathway inhibitors in combination with enzalutamide in a dose-dependent manner. NRG1-mediated resistance requires ligand activation and phosphorylation of the HER3 receptor as well as phosphorylation activity of HER2, and can be abrogated by treatment with anti-HER3 antibody seribantumab, knockdown with HER3 siRNA, or treatment with anti-HER2 inhibitor lapatinib. In 22RV1 cell line xenografts, combination therapy with seribantumab, enzalutamide, and pictilisib significantly suppressed tumor growth compared to enzalutamide and pictilisib alone. Conclusions: The TME-derived secretome plays a critical role in modulating resistance to targeted therapies in prostate cancer. NRG1 in the PCa TME, activates HER3 signaling and promotes resistance to both AR and PI3K pathway inhibitors. Targeting NRG1-HER2/3 signaling in combination with PI3K inhibitors represents a promising therapeutic strategy to overcome NRG1-mediated resistance mechanisms in advanced prostate cancer.

Machine learning models combining ⁶⁸ Ga-PSMA PET radiomics and clinical features to predict overall survival for mCRPC patients treated with ¹⁷⁷ Lu-PSMA radioligand therapy.

215 Background: Metastatic castration-resistant prostate cancer (mCRPC) remains incurable despite recent therapeutic advances. 177 Lu-PSMA radioligand therapy (RLT) provides meaningful clinical benefit in selected patients, yet approximately 30% show limited or no response. Although various baseline prognostic factors are well known, reliable pre-therapeutic predictive biomarkers are still lacking. Among emerging solutions, radiomics—by extracting quantitative imaging features—offers a novel approach to capture tumor heterogeneity and predict outcomes beyond standard visual assessment. To address this need, we developed and compared several predictive machine learning models integrating clinical, biochemical, and imaging data—including 68 Ga-PSMA PET radiomic features—to estimate overall survival in mCRPC patients treated with 177 Lu-PSMA RLT. Methods: This retrospective monocentric study included 102 mCRPC patients treated with 177 Lu-PSMA between January 2022 and March 2024. Five lesions per patient were segmented on their pre-therapeutic 68 Ga-PSMA PET/CT. Radiomic features were extracted following IBSI guidelines. Associations with OS were evaluated using Cox proportional hazards models. Multimodal machine learning (ML) models integrating clinical, genomic, biochemical, and imaging features (including radiomics) were developed to predict OS. Results: Median OS of the total cohort was 11.2 months. Intralesional homogeneity characterized by 2nd order radiomic feature “Normalized Inverse Difference Moment” was associated with shorter OS (p=0.025). Among clinical parameters, ECOG ≥2, liver metastases, and high tumor burden (≥20 metastases or superbone scan) were significantly correlated with poor OS (p&lt;0.05). The model leveraging PET data alone achieved strong performance, with a 12-month AUC comparable to the clinical model (0.715 vs 0.766). The best-performing ML model achieved a 12-month AUC of 0.778 by combining 22 clinical, biochemical, genomic, and radiomic features. Conclusions: Machine learning models based on 68 Ga-PSMA PET data, including radiomic features, offer a non-invasive, standardized, and widely accessible approach to predict survival in mCRPC patients treated with 177 Lu-PSMA RLT. Imaging-only models achieved performance comparable to clinical–biochemical models, providing robust prognostic information even in the absence of extensive clinical or molecular data. This highlights the strong predictive potential of PSMA PET imaging for patient stratification in real-world settings. Furthermore, radiomic characterization of intratumoral heterogeneity adds independent prognostic value, supporting the integration of imaging-derived biomarkers into personalized treatment decision-making.

A phase 2 multicenter, open-label study evaluating the efficacy and safety of dabogratinib (TYRA-300) in participants with FGFR3-altered low-grade, intermediate risk non-muscle invasive bladder cancer (SURF302).

TPS886 Background: Intermediate risk non-muscle invasive bladder cancer (IR NMIBC) is characterized by a high prevalence of activating fibroblast growth factor receptor 3 (FGFR3) mutations and fusions, with up to 80% of cases harboring these alterations (Szklener, 2022). FGFR signaling has been shown to play a crucial role in tumorigenesis and progression of cancer. Targeting FGFR3 may be particularly relevant in IR NMIBC, where novel therapeutic approaches are needed to reduce recurrence and progression. Recently, several pan-FGFR inhibitors have received regulatory approvals across multiple cancers, including erdafitinib in advanced urothelial carcinoma. These compounds are limited by tolerability due to a wide array of adverse events due to nonspecific inhibition. Dabogratinib is a highly selective inhibitor of FGFR3 with significantly lower activity against FGFR1, FGFR2, and FGFR4. Dabogratinib was designed to be selective for FGFR3 and less potent for the other FGFR isoforms, which may offer a differentiated safety profile suitable for the IR NMIBC setting. Methods: SURF302 (NCT06995677) is an open-label, Phase 2, global study that is designed to explore oral dabogratinib as monotherapy in patients with low grade IR NMIBC with activating FGFR3 pathway alterations. Adult patients with confirmed low grade IR NMIBC, at least 1 marker lesion, documented FGFR3 mutation or fusion, no evidence of upper tract disease and adequate organ function are generally eligible. Participants with a history of muscle invasive bladder cancer or metastatic disease, have presence of disease in the ureter or prostatic urethra or have received prior FGFR inhibitor therapy are excluded. The primary endpoint is the 3-month complete response rate in this population. Additional secondary endpoints include duration of response, safety and tolerability, and recurrence-free survival. Two doses will be initially tested (50 and 60 mg QD, n=30 each) in a randomized fashion. The study is planned for approximately 36 centers in North America, Australia, and Europe. Clinical trial information: NCT06995677 .

O ₂ ‐Accessible Fe–N ₄ Active Site Density Boosts Efficient Oxygen Reduction to Fuel‐Cell Level

ABSTRACT Not all sites with intrinsic activity show efficacy in practical catalysis due to inaccessibility or diffusion limitation, necessitating rational design of well‐connected hierarchical nanostructures to guarantee accessibility. Herein, the case is thoroughly investigated by way of atomically dispersed Fe–NC catalysts for the dominant O 2 gas‐consuming reduction (ORR). A pH‐dependent nanostructure manipulation strategy was developed to form solid, yolk‐shell, and hollow Fe–NC structures with similar overall density of quasi‐homogeneous Fe–N 4 sites, providing a comparative platform to investigate O 2 mass transport during ORR. Despite similar Fe loading, y‐Fe/NC structures achieve optimized O 2 ‐accessible active site density (ASD) due to fine‐tuned porosity and connectivity for sufficient O 2 accessibility. This observation is re‐affirmed by the observation of a relatively high j d for the y‐Fe/NC, which exceeds the theoretical value of a laminar flow pattern. This can be attributed to the increased O 2 ‐accessible ASD, originated from the local recirculation effect induced by the unique structure. Consequently, the y‐Fe/NC exhibits half‐wave potential of 0.82 V and j d of 7.66 mA cm −2 , outperforming counterparts and state‐of‐the‐art catalysts. Moreover, the optimized y‐Fe/NC remains effective in fuel cell with power density of 1.03 W cm −2 , demonstrating the essential roles of rationally designed nanostructures.

Gradient‐Modified Li‐Rich Manganese‐Based Oxides Cathodes with Breakthrough of Kinetic Limitation for High‐Performance All‐Solid‐State Lithium Metal Batteries

ABSTRACT The Li‐rich manganese‐based oxides (LRMO) with high operating voltage and large reversible capacities can demonstrate comprehensive advantages of intrinsic safety and high energy density when employed in all‐solid‐state lithium batteries (ASSLBs). However, severe interfacial incompatibility with solid electrolytes (SEs) arising from unstable lattice oxygen and sluggish Li + ionic transport hinders their practical application. In this contribution, the gradient‐modified structure containing S, Zr co‐doping near‐surface and amorphous Zr(SO 4 ) 2 coating is simultaneously established onto LRMO cathode by a one‐step mechano‐fusion process. The synergistic co‐functionalization stabilizes the oxygen framework, enhances charge transport, and suppresses oxygen dimerization under high potential. Besides, the amorphous Zr(SO 4 ) 2 coating evenly adhering onto LRMO bulk ensures long‐term intimate contact with SEs to guarantee electrochemical activities and restrains interfacial parasitic reactions. Consequently, the optimized A‐LRMO cathode exhibits a high discharge capacity of 292 mAh/g at 0.1 C and 81.8% capacity retention after 2000 cycles at 1 C. Pouch cells delivered an areal capacity of 8.5 mAh/cm 2 with &gt;99.6% Coulombic efficiency. This gradient‐modification strategy offers an effective pathway to improve interfacial stability and accelerate the practical application of LRMO‐based ASSLBs.

Nucleosome linker DNA methylation by DNMT3A/DNMT3B3 is controlled by nucleosome binding and multimerization of DNMT3 complexes on DNA

Multi-omic remodeling of urine-exposed ileal mucosa after ileocystoplasty.

856 Background: Ileal segments are widely used for urinary diversion, yet long-term dysfunction (increased residual urine volume, low compliance, mucus burden, infections) persists. How chronic urine exposure remodels the mucosal microenvironment across histology, microbiome, and cellular programs remain unclear. Methods: Rat ileocystoplasty with assessments at 1 week, 1 month, and 6 months. Ultrasound measured reservoir size; In vitro length by ruler. H&amp;E counted goblet cells per 100 nuclei; Masson quantified collagen fraction and total muscle thickness (blinded review). 16S rRNA sequencing at 1 month (ileum vs urine-exposed). Single-cell RNA-seq at 6 months (bladder/ileum/urine-exposed ileum). Statistics in R. Results: At 6 months, ileal segment length increased from 1.25 cm (1 week) to 1.62 cm (Δ 0.37 cm, +29.6%; p &lt; 0.05). Goblet cells per 100 nuclei declined from 43 (normal) to 10 at 1 month and 9 at 6 months (−76.7%, −79.1%; p &lt; 0.05 to &lt; 0.01). Collagen fraction was 0.16 (normal), 0.17 (1 month; not significant), and 0.27 (6 months; Δ +0.11, +68.8%; p &lt; 0.05). Total muscle thickness measured 1.12 at 1 month (vs 1.00; not significant) and 0.37 at 6 months (−63.0% vs normal; −67.0% vs 1 month; p &lt; 0.001). At 1 month, α-diversity decreased (Chao1 22 vs 45, −51.1%; Simpson 0.705 vs 0.765, Δ −0.060; Shannon 2.05 vs 2.75, Δ −0.70) without β-diversity separation (PERMANOVA p = 0.304; PC1 39.9%, PC2 23.2%). Communities showed fewer spore-formers and Romboutsia, with Propionibacteriales enrichment (LEfSe LDA 3.0). Random forest ranked Cutibacterium acnes highest (MeanDecreaseGini 0.28). Single-cell RNA-seq at 6 months showed epithelial cells 70%→30% and fibroblasts 15%→55%, with B/T cells nearly absent. Pseudobulk correlations indicated urine-exposed epithelium was closer to bladder than native ileum (r = 0.80 vs 0.55; similar trends for fibroblast and smooth muscle). Marker programs supported mechanosensory–serotonergic rewiring with Cga, Slc6a4, Piezo1, Piezo2 up and Tph1 down; lineage specificity included Slc6a4 19% in epithelium, Piezo1 20% in neurons, and Piezo2 15% in endothelium (P &lt; 0.001). Conclusions: Chronic urine exposure drives reservoir enlargement with fibrosis, goblet-cell loss, and microbiome simplification, alongside bladder-like and fibrosis cellular programs (extracellular matrix, Hippo activation). These data provide a new perspective and theoretical basis for the postoperative management of orthotopic ileal neobladder.

Non-invasive prostate cancer subtyping using 5hmC-sequencing of cell-free DNA.

242 Background: Optimizing treatment for metastatic castration-resistant prostate cancer (mCRPC) requires knowledge of different lineage subtypes such as androgen receptor (AR)- positive prostate cancer (ARPC), neuroendocrine prostate cancer (NEPC) and double-negative prostate cancer (DNPC). However, metastasis biopsies are not always available. Epigenetic and genetic characterization of cell-free DNA (cfDNA) has the potential to non-invasively classify tumor subtypes to help guide precision oncology and monitor tumor evolution. In this study, we sought to assess whether using cfDNA 5-hydroxymethylcytosine sequencing (5hmC-seq) non-invasively predicts tumor subtypes and signaling defined in matched tissue from men with mCRPC. Methods: We performed 5hmC-seq and low-pass whole-genome sequencing (lpWGS) of plasma-derived cfDNA from 86 mCRPC patients with matched tumor tissue profiled with 5hmC-seq (N = 49) and RNA-seq (N = 86). We developed a 5hmC-seq based Random Forest-based hierarchical classifier to distinguish ARPC, NEPC and DNPC. The previously published Griffin and ctdPheno tools were used to classify samples based on lpWGS. The locked classifiers were evaluated in a separate cfDNA cohort from men with mCRPC (N = 64). Results: Samples with less than 10% circulating tumor DNA fraction (ct-fraction) were categorized as a good prognosis group, while the rest samples were used for classifier training and testing (ARPC (N = 22), NEPC (N = 6) and DNPC (N = 11)). The 5hmC-based Random Forest subtype classifier reached an AUC of 0.89 [95% CI 0.73-1.0] and 0.88 [95% CI 0.76-1.0] for NEPC and DNPC prediction in cross-validation, respectively. The 5hmC-based predicted subtype in the separate validation cohort was strongly prognostic for overall survival (OS); NEPC compared to ARPC HR = 17.3 [95% CI: 2.0 – 147.9], p = 9.1 x 10-3, and DNPC compared to ARPC HR = 34.7 [95% CI: 5.3 – 225.6], p = 2.1 x 10-4, adjusting for ct-fraction. Furthermore, high 5hmC-seq NE score in cfDNA predicted shorter OS (HR = 8.3 [95% CI: 1.1 – 61.8], p = 0.038), while high 5hmC-seq AR score predicted longer OS (HR = 0.26 [95% CI: 0.09 – 0.75], p = 0.013), adjusting for ct-fraction. Concurrently sequenced lpWGS demonstrated that the ratio of short (&lt; 150 bp) vs. long (150 ~ 220 bp) fragments was higher in NEPC compared to other subtypes at the similar ct-fraction (ANOVA test P = 0.0017). ARPC showed low central coverage at AR binding sites, while NEPC exhibited low central coverage at ASCL1 binding sites. DNPC displayed no signal at either binding site. The predicted subtypes based on nucleosome positioning patterns from lpWGS were concordant with that predicted by 5hmC-seq in the separate cohort. Conclusions: cfDNA 5hmC-seq based classifiers successfully identified tumor phenotype, classified tumor subtypes concordant with matched tissue and were prognostic. This non-invasive approach enables sequential monitoring of lineage plasticity during mCRPC progression.