Browse Articles

Opto‐Ferroelectric Coupling Enhanced α‐In ₂ Se ₃ Transistors With Light‐Controlled Mode Switchover

ABSTRACT Neuromorphic computing is an ideal approach for achieving complex pattern recognition works; however, it is usually incompatible with digital logic processing units, limiting its application scope. Leveraging an opto‐ferroelectric coupling enhanced effect, we herein achieve the light‐controlled mode switchover between logic processing and neuromorphic computing in a ferroelectric transistor with α‐In 2 Se 3 /h‐BN as gate dielectrics and MoS 2 as channel. Under dark conditions, the transistor operates in digital logic mode with a high current on/off ratio of 10 9 , ultra‐low subthreshold swing (SS) of 33 mV/dec, and low leakage current of 5.6 × 10 −13 A, which is promising for logic processing applications. The inverter and NOR circuits with high noise margin and low power consumption were further implemented via interconnecting n‐ and p‐type transistors. Under light conditions, the ferroelectric polarization field of α‐In 2 Se 3 is significantly enhanced, leading to an enlarged hysteresis window (Δ V ) and switching the transistor into an optoelectronic synapse mode for neuromorphic computing, which can support image classification with an accuracy of up to 94.43% and a low energy consumption of 0.47 pJ/spike. This work provides an opto‐ferroelectric coupling‐enhanced transistor that addresses the incompatibility issue between digital logic and neuromorphic computing units, offering a new pathway for next‐generation computing devices.

Biomimetic Nanometer‐Size All‐Liquid Channels

ABSTRACT A wealth of micro/nanoscale fluidic channels between/in cells maintain essential mass transfer processes, ensuring the proper functioning of living organisms. Nevertheless, the artificial construction and simulation of such all‐liquid channels remain, yet, a formidable challenge, due to the inherent Plateau–Rayleigh instability. Here, we present a new “quasistatic stretching” approach applied to a liquid bridge in another immiscible liquid, where the liquid/liquid interfaces were manipulated by interfacial nanoparticle–polymer coassemblies. These coassemblies, with characteristic of reconfigurable, tunable jammed networks, enable stepwise stretching the channel in liquid bridge size downward. We establish a selection rule of component inputs that yield ultrafine liquid channels during the stretching process. The superior flexibility and moderate entanglement or cross‐linking of polymer chains within the nanoparticle–polymer microstructures endow the liquid bridge with plastic deformability, allowing the channel forward to hundred nanometer size, reducing by two‐orders‐of‐magnitude on state‐of‐the‐art technology and approaching the size range of biomimetic counterparts. Furthermore, biomimetic functions—intercellular mitochondrial rescue and compartmentalized immunotherapy—were proved using the organism tubular analog—liquid bridge based channels, via controlling the flowrate of the mass transfer in the channels. These simulations may offer a potential framework for biophysically understanding cellular processes mediated by tubular structures.

Disruptions of cell signaling pathways in myotonic dystrophy type 1 skeletal muscle, their pathogenic impact, and potential for combinatorial therapeutics

A rules-based AI triage system to identify NCCN-indicated genetic testing in prostate cancer: A performance analysis.

54 Background: Somatic and germline testing in prostate cancer can inform overall prognosis, treatment sequencing decisions, and familial risk through cascade testing. Despite clear guidelines from organizations like the AUA, ASCO and NCCN, a significant gap remains between recommendations and clinical practice, with two-thirds of men in the US with metastatic prostate cancer not receiving consensus guideline compliant testing. This study evaluates a rules-based artificial intelligence (AI) system that identifies patients who meet NCCN criteria for somatic and germline testing, with the end goal of improving adherence to the clinical guideline. Methods: We developed a rules-based AI (ChatGPT 5.0) system to mirror NCCN v1.2023 guidelines on somatic and germline testing for prostate cancer, producing three actionable states: "indicated," "consider," and "not indicated.” Structured inputs included age at diagnosis, TMN stage, current risk group, grade, and nodal/metastatic status. Somatic rules: indicated if M1; consider if castration-resistant prostate cancer (CRPC) without M1, N1, or localized high/very high-risk disease (T3a–T4, Grade Group ≥4, or PSA >20); otherwise not indicated. Germline rules: indicated if M1, N1, or localized high/very high risk; consider if intermediate risk with age ≤60 or CRPC without metastasis; otherwise not indicated. Metrics were assessed in a retrospective cohort of 259 prostate cancer patient charts seen at Oncology Hematology Care in 2023. Gold standard was manual review of patient charts. Results: Average age at diagnosis was 68 years and 54% of patients had stage IV disease. The AI system demonstrated high sensitivity and specificity. Germline false negatives (n=7) represented cases where testing was considered based on manual review of non-structured data, including family history. Conclusions: This rules-based AI demonstrated excellent performance in identifying NCCN-indicated genetic testing within a real-world cohort of 259 charts, achieving perfect accuracy for somatic testing and near-perfect accuracy for germline testing. Limitations include the retrospective, single-practice design and reliance on structured inputs. Overall, this approach is readily implementable and may improve guideline adherence; multi-site validation and EMR integration are planned. Accuracy of rules-based triage for NCCN-indicated genetic testing. TP FP FN TN Sensitivity (95% CI) Specificity (95% CI) Somatic 195 0 0 64 100% (98–100) 100% (94–100) Germline 208 0 7 42 96.7% (93–98) 100% (92–100)

Pathological outcomes and disease-free survival (DFS) in KEYNOTE-905: Neoadjuvant and adjuvant (neoadj-adj) enfortumab vedotin (EV) plus pembrolizumab (pembro) in participants (pts) with muscle-invasive bladder cancer (MIBC) who are cisplatin-ineligible.

638 Background: The phase 3 KEYNOTE-905/EV-303 study (NCT03924895) showed significantly improved EFS, OS, and pCR rate with neoadj-adj EV + pembro added to radical cystectomy with pelvic lymph node dissection (RC + PLND) in pts with MIBC who were cisplatin-ineligible. We report pathological outcomes and DFS in the study. Methods: Pts with T2-T4aN0M0 or T1-T4aN1M0 MIBC ineligible for or declining cisplatin were randomized 1:1 to EV + pembro (3 cycles neoadj EV 1.25 mg/kg on d 1 and 8 + pembro 200 mg on d 1, RC + PLND, and adj 6 cycles EV + 14 cycles pembro) vs control (RC + PLND only). pCR (absence of viable tumor in tissue from RC + PLND [pT0N0]) rate was a key secondary endpoint; pathological downstaging (pDS; < pT2 [pT0, pTis, pTa, pT1] and N0) rate and DFS (time from post-surgery scan to local/distant recurrence or death) were secondary endpoints, all assessed by central pathology review or BICR. Pts were considered disease-free after RC + PLND for DFS analysis if they had complete resection (no gross residual disease) and no evidence of disease on a post-surgery scan. Results: As of June 6, 2025, median follow-up was 25.6 mo (range, 11.8–53.7). In the EV + pembro vs control arms, 149/170 pts (87.6%) and 156/174 (89.7%) underwent surgery; 147/149 (98.7%) and 149/156 (95.5%) had complete resection; and 138/149 (92.6%) and 123/156 (78.8%) had negative surgical margins. In addition to the previously reported pCR rate for all pts in the EV + pembro vs control arms (57.1% vs 8.6%; estimated difference 48.3%; 95% CI 39.5–56.5; P < .001), pDS rate was higher with EV + pembro vs control (65.9% vs 12.6%; estimated difference 53.1%; 95% CI 44.0–61.2). Table shows comprehensive pDS outcomes. Among pts evaluated for DFS (n = 135 in EV + pembro arm; n = 129 in control arm), median DFS was not reached vs 23.6 mo (HR 0.37; 95% CI 0.23–0.59). Conclusions: pCR, pDS, surgical outcomes, and DFS favored neoadj-adj EV + pembro and RC + PLND vs RC + PLND alone, supporting the primary results of KEYNOTE-905. These findings further establish neoadj-adj EV + pembro as a potential standard of care for pts with MIBC who are cisplatin-ineligible, addressing a key unmet clinical need. Clinical trial information: NCT03924895 . N; % (95% CI) EV + pembro, N=170 Control, N=174 pDS (<pT2N0) 112 65.9 (58.2–73.0) 22 12.6 (8.1–18.5) pT0N0 97 57.1 (49.3–64.6) 15 8.6 (4.9–13.8) pTisN0 7 4.1 (1.7–8.3) 2 1.1 (0.1–4.1) pTaN0 1 0.6 (0.0–3.2) 0 0.0 (0.0–2.1) pT1N0 7 4.1 (1.7–8.3) 5 2.9 (0.9–6.6) Non-pDS (≥pT2N0) 33 19.4 (13.8–26.2) 112 64.4 (56.8–71.5) Other* 2 1.2 (0.1–4.2) 15 8.6 (4.9–13.8) Incomplete resection 2 1.2 (0.1–4.2) 7 4.0 (1.6–8.1) Did not undergo surgery 21 12.4 (7.8–18.3) 18 10.3 (6.2–15.9) *Not evaluated centrally for pDS due to no available evaluable surgical sample, nonprotocol systemic therapy prior to RC + PLND or operational issues; considered non-pDS in analysis.

End-of-life treatment patterns in patients with advanced urothelial carcinoma.

687 Background: Immune checkpoint inhibitors and antibody-drug conjugates have expanded therapeutic options for advanced urothelial carcinoma (aUC); however, prognosis remains poor. Data on end-of-life treatment patterns in this setting are limited but are critical to inform clinical decision-making and optimize quality of care. Herein, we aimed to evaluate real-world treatment patterns in relation to the time of death in patients (pts) with aUC in a large US-based database. Methods: This study used the US-based, electronic health record-derived deidentified Flatiron Health Research Database. Eligibility: pts who were diagnosed with aUC, initiated first-line (1L) therapy, and had a recorded date of death. The data cut-off date was 6/30/2025. Pts were categorized into two groups: treatment-free, if no systemic therapy was administered during the last 3 months of life, or on-treatment, if systemic therapy was received within 3 months preceding death. Demographic and clinical variables at their last line of therapy (LOT) initiation, including age, race, region, socioeconomic status, practice type, and insurance, were summarized using medians (IQR) or proportions. Comparisons were performed using Wilcoxon rank-sum or chi-squared tests. Results: Among 15,236 pts with aUC diagnosed between 1/1/2011 and 5/8/2025 in the dataset, 7,815 were eligible and included in the final analysis. Of these, 5,221 pts (66.8%) received systemic therapy within 3 months of death (on-treatment), while 2,594 pts (33.2%) did not (treatment-free). At the time of last LOT initiation, treatment-free pts were older than those on-treatment (median age 75 years [IQR 68–81] vs. 74 [IQR 67–80], p = 0.042). Pts in the on-treatment group were more often treated in community practice (85% vs 82%, p = 0.005) and more likely to have commercial health plan (60% vs 57%, p < 0.001). Among on-treatment pts at end of life, the most common last regimen was single agent programmed cell death protein 1 (PD-1) inhibitors (42%), followed by carboplatin-based (17%), and cisplatin-based therapies (8%). Further baseline characteristics and treatment patterns will be presented at the meeting. Conclusions: Our data show that over two-thirds of pts with aUC continued systemic therapy within 3 months of death. Importantly, ~25% of these were still receiving platinum-based therapies. These findings highlight the importance of realistic treatment goals and the need to balance potential benefit with quality of life in the final months of life. Limitations include retrospective nature of study and possible data missingness.

Real-world comparative outcomes of abiraterone vs enzalutamide in metastatic castration-sensitive prostate cancer (mCSPC): A propensity-matched analysis from the TriNetX Global Health Research Network.

124 Background: Abiraterone acetate (ABI) and enzalutamide (ENZ) have each demonstrated survival benefit in patients with metastatic castration-sensitive prostate cancer (mCSPC), supported by pivotal trials such as LATITUDE, STAMPEDE, and ENZAMET. However, these trials did not directly compare the two agents. Real-world data (RWD) evaluating comparative survival, safety, and rare outcomes such as treatment-emergent neuroendocrine prostate cancer (t-NEPC) remain limited. This study aims to compare clinical outcomes between ABI and ENZ using a global, multicenter RWD. Methods: We conducted a retrospective cohort study using the TriNetX Global Health Research Network, a federated database encompassing electronic medical records from 154 healthcare organizations. Men with mCSPC treated with ABI or ENZ from database inception through June 2025 were identified. Propensity score matching (1:1) was performed based on age, race, ECOG status, PSA, BMI, and comorbidities. The primary outcome was all-cause mortality; secondary outcomes included hospitalization, adverse events (AEs), and incidence of t-NEPC. Time-to-event outcomes were analyzed using Kaplan-Meier and Cox regression methods. Results: Among 5,344 eligible patients (ABI: 2,831; ENZ: 2,513), 2,403 patients were retained in each matched group. The median age was 71.5 years; median follow-up was 426 days (ABI) vs 435 days (ENZ). All-cause mortality was similar between ABI and ENZ (38.49% vs 39.01%; HR 1.006, 95% CI: 0.918–1.102; p = 0.862). Hospitalization rates (46.65% vs 44.99%; p = 0.247) and Kaplan-Meier survival curves were not significantly different (log-rank p = 0.9002). Fatigue (31% ABI vs 34% ENZ) and falls (7% vs 8%) were slightly more common with ENZ, while hypertension was marginally higher in the ABI group (2% vs 1.8%). The incidence of t-NEPC was nearly identical (ABI: 18.67% vs ENZ: 18.76%; RR 0.996, 95% CI: 0.886–1.119; p = 0.94). Docetaxel exposure was similar across both cohorts (ABI: 15% vs ENZ: 16%), suggesting comparable use of subsequent lines of therapy. Conclusions: In this large, global real-world cohort of mCSPC patients, abiraterone and enzalutamide showed comparable survival and hospitalization outcomes, with no significant differences in t-NEPC transformation. This data supports therapeutic equivalence and suggests treatment selection may be best guided by individual patient factors, tolerability profiles, and shared decision-making.

Waste to Catalyst: Tuning Structure and Composition of Ferrous Scrap‐Derived Alloys by Rapid Solidification for Advanced Catalysis

ABSTRACT A significant amount of ferrous scrap resources remain unrecycled, and the abundant iron content gives them potential as environmental catalysts. However, the practical application of ferrous scrap in catalysis remains a significant challenge. Herein, a strategy based on rapid solidification to increase the specific surface area, regulate the microstructure, and introduce high residual stress in ferrous scrap is proposed, leading to enhanced catalytic performance. The introduction of high residual stress and the construction of an amorphous structure significantly enhance performance, enabling a degradation efficiency of 98% within 40 s and a high k obs of 5.866 min −1 . Theoretical calculations reveal that progressively optimizing the phase structure—from the α ‐phase to the ε ‐phase and then an amorphous phase—promotes persulfate (PS) adsorption, and significantly enhances the electron transfer capability. Furthermore, optimizing the composition of the catalyst improves its stability to 30 cycles and develops a novel catalyst with dual functionality for both pollutant degradation and water electrolysis, exhibiting an oxygen evolution reaction (OER) overpotential η 10 of 309 mV. These findings provide a new perspective for the recycling of ferrous scrap and offer innovative ideas for developing multifunctional catalytic materials, which are capable of addressing integrated challenges in water treatment and clean energy conversion.

Deciphering Atomic Electronic Structure Dynamics and Site Occupancy Transitions in Dictating Sodium Storage in Hard Carbon

ABSTRACT Deciphering the hard carbon (HC) sodiation mechanism is essential for HC's rational design, but is confused by sodium insertion and pore‐filling in the plateau region due to HC's microstructural heterogeneity. This work leverages high‐resolution 13 C NMR and operando 23 Na NMR, which identify the carbon layer lining the micropore‐wall as a contributor to HC's electronic structure beyond the quasi‐metallic sodium clusters during the early plateau region. The stage coincides with a sodium occupancy transition of Na + initially residing in graphitic interlayers into sodium clusters in micropores. The synergy of these changes consequently leads to the reduction of the Na + diffusion coefficient. These results demonstrate how the carbon matrix itself, not just the pore architecture, controls the critical plateau electrochemistry in HC. Moreover, these findings provide conclusive evidence for an advanced theoretical framework of HC sodiation through three stages, and underscore the tailoring of electronic environments and Na occupancy for advanced HCs.

Engineered IgA-Fc fusion protein with bioactive nanobody neutralizes SARS-CoV-2 variants with mucosal delivery potential

Non-cancer causes of death in patients with hormone-sensitive prostate cancer.

55 Background: The overall survival of men with metastatic hormone-sensitive prostate cancer (mHSPC) has been significantly improved, while a substantial proportion of patient’s deaths are non-cancer-related. Characterizing the causes of non-cancer related deaths may guide preventive and supportive strategies. Methods: We performed a retrospective multicentric study of all patients (pts) diagnosed with mHSPC between 2010 and 2025 who received androgen deprivation therapy (ADT) alone, ADT + docetaxel, ADT + androgen receptor pathway inhibitors (ARPI), or triplet therapy. Clinical and tumor data, comorbidities and mortality information were extracted from electronic medical records. Deaths were classified as PC–related or non-cancer; non-cancer deaths were subclassified (infectious, cardiovascular, respiratory, other cancer, unknown; single-category causes pooled as “Miscellaneous”). Overall survival (OS) was estimated by Kaplan–Meier. Group comparisons used Kruskal–Wallis for continuous variables and Fisher’s exact test for categorical variables. Results: Among 565 pts with mHSPC, 93 received ADT alone, 125 ADT plus docetaxel, 321 ADT plus ARPI, and 26 triplet therapy (ADT + docetaxel + ARPI). During a median follow-up of 44.6 months (4.5 - 228.9), 382 pts (68%) died. Thirty-five deaths (6.2% of pts, 9% of deaths) were attributed to non-cancer causes before progression to castration-resistant prostate cancer (CRPC). Median OS in this subgroup was 16 months (95% CI: 12.6–43.8). Leading causes were infectious (12/35, 34%; 17% Covid-19), cardiovascular (6/35, 17%), other cancer (5/35, 14%), unknown cause (4/35, 11%), and respiratory (3/35, 9%); the remaining single-category causes (neurological, trauma, pulmonary embolism, digestive, euthanasia) totaled 5/35 (14%). No deaths were attributed to febrile neutropenia. Pts who died of cardiovascular causes tend to have a lower median age at death compared to those with infectious disease (72 vs 83.5 years respectively). They also showed higher functional status (median Barthel 100 vs. 60) and a lower comorbidity status (median 2 vs. 3), although non significant. Most pts (71%) were on active systemic therapy at the time of death, most commonly ADT + ARPI (46%). No significant differences were observed between cause of death and treatment received. Conclusions: Non–cancer related deaths occurred in 6% of mHSPC patients, mainly due to infections and cardiovascular events, the latter potentially linked to ADT and ARPIs. These findings highlight the importance of early cardiovascular risk assessment and preventive interventions to improve survival in this population.

Predictors and clinical outcomes of renal tumor upstaging from cT1 to pT3a disease in patients who underwent robot-assisted partial nephrectomy.

558 Background: Robot-assisted partial nephrectomy (RAPN) is the standard treatment of small renal masses, offering favorable perioperative, oncological, and functional outcomes. Nevertheless, there remains a risk of kidney cancer upstaging that may influence oncological outcomes. This study evaluates the incidence, risk factors, and clinical outcomes of RAPN patients who were upstaged from cT1 to pT3a. Methods: A retrospective review of a prospectively maintained, IRB-approved database was reviewed to identify all cases of cT1 renal mass managed with RAPN between 2006 and 2023. Risk factors for cT1/pT3a upstaging were analyzed with logistic regression analyses, and overall and recurrence-free survival outcomes with Kaplan-Meier analysis. Results: Of the 1414 patients with cT1 renal masses, 134 (9.4%) were upstaged to pT3a. Upstaged patients were older (median 64.6 vs. 60 years, p=0.011), had higher comorbidity burden (CCI 2 vs. 1, p<0.001), greater tumor complexity (RENAL 8 vs. 6, p<0.001), and more frequent positive margins (17.2% vs. 5.3%, p<0.001). On multivariable analysis, larger tumor size (OR 1.14; 95% CI 1.05–1.27, p=0.005) and hilar location (OR 1.36; 95% CI 1.02–1.81, p=0.036) independently predicted upstaging. At median follow-up of 38 months, recurrence was more frequent in upstaged patients (3.8% vs. 1.8%, p=0.19). Conclusions: In patients with cT1 renal mass undergoing RAPN, upstaging to pT3a disease represents an uncommon event. Despite the low incidence, cT1/pT3a upstaging may translate to worse oncological outcomes, including positive surgical margins and a higher risk of disease recurrence. When considering the risk factors, both larger tumor diameter and hilar locations have emerged as independent predictors of pathology upstaging to pT3a. Baseline clinicodemographic and outcomes of all included patients. Upstaging( n = 134) No Upstaging( n = 1280) p Age (years) 64.6 (54.8 – 70.1) 60 (51.8 – 68) 0.01 BMI (kg/m 2 ) 31.2 (26.7 – 35.9) 29.9 (26.3 – 34.9) 0.25 Gender (Male) 87 (64.9%) 809 (63.2%) 0.76 CCI 2 (0 – 4) 1 (0 – 3) <0.001 Smoking History 71 (53.4%) 622 (48.6%) 0.51 Baseline GFR (mL/min/1.73m 2 ) 77.4 (62.2 – 96.3) 80.1 (65.8 – 95.4) 0.14 RENAL Score 8 (6 – 9) 6 (5 – 8) <0.001  Low Complexity 46 (37.7%) 624 (54.1%)  Intermediate Complexity 56 (45.9%) 445 (38.6%)  High Complexity 20 (16.4%) 84 (7.3%) Largest Tumor Diameter (cm) 4 (3 – 4.8) 3 (2.2 – 4) <0.001 Positive Surgical Margin 21 (17.2%) 59 (5.3%) <0.001 Follow-up duration (months) 31 (17 – 62) 40 (19 – 66) 0.69 %GFR preservation at 12 months 80 (74.1 – 96.7) 90 (79.1 – 101.2) 0.03 Disease-specific recurrence 5 (3.8%) 22 (1.8%) 0.1 IQR = Interquartile Range; BMI = Body Mass Index; CCI = Charlson Comorbidity Index; GFR = Glomerular Filtration Rate; Categorical variables are presented as n (%), and continuous variables as median (IQR).

Assessing impact of RDI on outcomes in patients treated with enfortumab vedotin-pembrolizumab combination therapy.

689 Background: Enfortumab vedotin (EV) and pembrolizumab have emerged as first-line combination therapy for locally advanced or metastatic urothelial carcinoma (UC). In retrospective studies of EV monotherapy, higher relative dose intensities (RDI) in the initial treatment cycles have been associated with improved response rates and prolonged progression-free survival (PFS), whereas cumulative RDI across the entire treatment course has not shown a consistent relationship with outcomes. The impact of EV RDI on outcomes in combination therapy treated patients remains unclear. Our single-center, retrospective study aims to assess the relationship between RDI within the first 3 and 6 cycles and PFS and overall survival (OS). Methods: We conducted a retrospective analysis of patients treated with EV + pembrolizumab. Only patients who received >1 cycle of EV were included. Data on PFS, OS, and dosing were collected from the EMR. For each patient, cumulative RDI was calculated through cycle 3 (RDI-3) and cycle 6 (RDI-6) as: (delivered EV dose) / (standard EV dose during that timeframe) x 100%. The primary analysis evaluated RDI as a continuous variable in Cox regression models using 63-day and 126-day landmark analyses, corresponding to the completion of 3 and 6 cycles, respectively. Models were adjusted for ECOG status and assessed PFS and OS as endpoints. RDI-3 and RDI-6 were selected to capture early versus later effects of RDI and to align with institutional restaging practices. The Kaplan-Meier method was used to analyze survival by RDI group (RDI >80% and < 80%). The 80% threshold was selected as it represents the typical first EV dose reduction from 1.25 mg/kg to 1.00 mg/kg, consistent with prior EV monotherapy studies. These analyses were exploratory and supplemental to the primary analysis. Results: 104 patients met inclusion criteria. Of these, 90 and 99 were evaluable for RDI-3 PFS and OS landmark analyses, and 78 and 89 for RDI-6, respectively. The median follow-up time was 17.2 months. In adjusted landmark Cox models, higher RDI-3 and RDI-6 showed no significant difference in PFS (RDI-3: HR 0.903, p = 0.152; RDI-6: HR 0.987, p = 0.859) or OS (RDI-3: HR 0.891, p = 0.155; RDI-6: HR 0.895, p = 0.218). Unadjusted Kaplan–Meier analyses similarly showed no association between RDI and PFS or OS (RDI-3: PFS p = 0.61, OS p = 0.23; RDI-6: PFS p = 1, OS p = 0.48). Conclusions: In adjusted analyses, RDI over the first 3 and 6 cycles did not significantly correlate with PFS or OS. These findings contrast with prior EV monotherapy data, suggesting that, within the EV + pembrolizumab paradigm, early EV dose intensity may be less critical, allowing flexibility in dosing without compromising efficacy, potentially reflecting a compensatory effect from immunotherapy combination. HR (95% CI) p-value RDI-3  PFS 0.903 (0.79-1.04) 0.152  OS 0.891 (0.76-1.04) 0.155 RDI-6  PFS 0.987 (0.86-1.14) 0.859  OS 0.895 (0.75-1.07) 0.218

Clinical and biomarker characteristics of treatment-emergent neuroendocrine prostate cancer.

87 Background: Treatment-emergent neuroendocrine prostate cancer (tNEPC) arises as a phenotype of metastatic castration-resistant prostate cancer (mCRPC) under therapeutic pressure. Despite its poor prognosis, no consensus diagnostic criteria exist for tNEPC. Its clinical and molecular features remain unclear due to the rarity of disease. This study assessed clinical characteristics, biomarkers and outcomes of tNEPC as compared to adenocarcinoma (ACPC) in the mCRPC setting. Methods: This was a retrospective study of adult patients with tNEPC and a matched ACPC cohort (up to 1:2 ratio based on the biopsy date) diagnosed with mCRPC from 01/01/2013 to 12 months before data collection (04/15/2024-11/30/2024) at two US academic institutions. Biopsies obtained after mCRPC diagnosis (index biopsy) were reviewed by two central pathologists to confirm histological diagnosis, using pre-specified standardized definition and pathology criteria. Patients’ characteristics, immunohistochemistry (IHC) markers, treatments and outcomes were compared between tNEPC and ACPC. Results: This study included 79 patients (28 site-defined tNEPC and 51 matched ACPC). The majority were >65 years (mean age: 73 vs 72 years) and white (84% vs 83%), with comparable baseline clinical characteristics between groups. Median follow-up was 13.3 months (tNEPC 6.3; ACPC 15.6). The central pathologists confirmed site diagnoses in 76 patients (κ agreement= 0.91), leaving 71 matched patients (25 tNEPC [24 small cell carcinoma]; 46 ACPC) in the final analysis. All biopsies were metastatic and most came from the liver (tNEPC 44.0% vs ACPC 35.2%). For IHC markers, tNEPC patients had higher positivity of synaptophysin (92% vs 35%) and chromogranin (79% vs 33%), while NKX3.1 positivity was higher in ACPC (24% vs 97%). The most common first lines of therapy (1L) after index were platinum-based chemotherapy (50%) for tNEPC, and androgen receptor pathway inhibitors (53%) for ACPC, but 20% of tNEPC and 22% of ACPC had no record of mCRPC-specific treatments constituting a 1L. While PSA response (≥50% decline) in the post-index period was similar between tNEPC and ACPC (41% vs 42%), tNEPC patients had significantly worse overall survival (OS) after index than ACPC (median OS: 6.3 vs 14.7 months; HR=1.99, 95% CI 1.14–3.42). In tNEPC patients, NKX3.1 positivity appeared associated with better OS (HR=0.29; 95% CI: 0.1-0.9). Conclusions: tNEPC shows distinct histological and IHC profiles, treatment patterns, and worse OS compared with ACPC. These findings highlight important unmet medical need in tNEPC. While the high concordance between central review and site pathologists’ review could be due to expertise in genitourinary/prostate pathology at the academic institutions, our results suggest standardized histopathologic criteria for tNEPC, along with IHC markers, help improve disease classification and diagnostic accuracy in clinical practice.

Revealing the Defect‐Driven Ferroelectric Mechanisms of Aluminum Nitride

ABSTRACT Wurtzite III‐nitride compounds are CMOS‐compatible with widespread industrial interest to exercise ferroelectricity, despite their polar structure being highly resistant to polarization reversal. Here, we induce and tune ferroelectric properties in w‐AlN via direct‐write ion‐beam processing, using nanoscale patterned defect engineering as a post‐growth alternative to conventional cation substitution. Nanometric piezoresponse spectroscopy of the focused He + beam patterned defect concentrations in ferroelectric Al 0.92 B 0.08 N measures a localized 10x enhancement in effective piezoresponse and 40% reduction in switching barrier. The irradiation‐induced point defects convert piezoelectric AlN into a ferroelectric system with site‐saturated nucleation and raise the dielectric susceptibility, switched polarization, and effective piezoelectric coefficient. Enhanced defect‐lattice interactions in AlN increase carrier conduction and phonon scattering loss but preserve long‐range crystallinity. Based on atomistic analysis of nudged elastic band density functional theory calculations and reactive force field simulations, both nitrogen vacancies and defect complexes disrupt bond ordering, facilitating a line‐by‐line low‐barrier switching of pristine AlN.

Ordered Heterogeneous Interfaces Enable Temperature‐Insensitive and Ultrahigh‐Energy‐Storage Multilayer Ceramic Capacitors

ABSTRACT Achieving both high energy storage density and excellent thermal stability in lead‐free multilayer ceramic capacitors (MLCCs) has long been a critical challenge for advanced electronic systems. To address this issue, we propose an innovative strategy to simultaneously improve both properties by constructing ordered heterogeneous interfaces through embedding parallel‐aligned Al 2 O 3 plates in 0.6SrTiO 3 ‐0.4Bi 0.5 Na 0.5 TiO 3 (0.6ST‐0.4BNT) lead‐free ceramics. This approach effectively suppresses the charge carrier injection and transport, yielding an ultrahigh recoverable energy storage density of 16.0 J cm −3 with a giant breakdown strength of 1140 kV cm −1 in Al 2 O 3 modified 0.6ST‐0.4BNT based MLCCs, which outperforms most state‐of‐the‐art dielectric ceramics. Furthermore, the MLCCs exhibit superior thermal stability with variation less than 3% across a broad temperature range of 20–160 °C. The overall superior performance underscores the potential of the ordered heterogeneous interface engineering in advancing the thermally stable high‐density energy storage materials for next‐generation MLCC applications.

A cell-based assay for retinaldehyde dehydrogenase activity: Retinoid quantification as an alternative to current fluorescence-based approaches

Spatially resolved HER2 and AR expression in prostate cancer and its implications for HER2 as a distinct therapeutic target.

385 Background: Androgen receptor (AR) target genes are re-expressed during androgen deprivation therapy which stimulates prostate cancer (PC) proliferation. A promising area of investigation focuses on inhibiting androgen-independent signaling pathways—such as human epidermal growth factor receptor 2 (HER2/ ERBB2 )—that promote metastasis. We recently described the role of HER2 in PC and appealed for deeper investigation in diverse populations. HER2 is a well-characterized oncogenic driver in multiple cancer types, including PC. The higher prevalence of HER2 overexpression among Black men with PC has recently come to light, while differences in AR expression and function in Black men has been more well-described. In this study, we utilized spatial transcriptomics to evaluate basal HER2 and AR expression in a racially diverse patient-derived xenograft (PDX) model as well as immunofluorescence to evaluate changes in HER2 and AR induced with HER2 drug targeting in a diverse panel of PC cell lines. Methods: To resolve the spatial dynamics of ERBB2, AR, and other relevant gene expression in PDXs, we utilized the 10x Genomics Xenium In Situ spatial transcriptomics platform. Tissue sections were processed using Xenium’s 377-gene Human Multi-Tissue Cancer panel, augmented with prostate-specific and ERBB2 -related targets. To assess the effects of HER2 drug targeting on HER2 and AR expression, we performed immunofluorescence staining in treated vs. untreated LNCaP, MDA-PCa-2b, and 22Rv1 PC cell lines. Results: Spatial transcriptomic analysis revealed that the ERBB2 and AR transcript burden per tumor area were significantly higher in a PDX developed from a Black patient compared to a PDX developed from a white patient. Immunofluorescence revealed HER2 was abundantly expressed in the cytoplasmic and membranous compartments of all three cell lines, while AR was strongly localized within the nuclei, consistent with its transcriptional activity and confirmed distinct yet partially overlapping subcellular distributions of HER2 and AR. HER drug targeting led to a consistent reduction in HER2 signal intensity across all models. In LNCaP and 22Rv1 cells derived from white patients, HER2 drug targeting markedly diminished HER2 staining, coinciding with a reduction in nuclear AR signal intensity. MDA-PCa-2b cells derived from a Black patient also exhibited decreased HER2 expression following HER2 drug targeting, with a concurrent modest reduction in AR intensity. This result revealed diminished HER–AR colocalization after HER2 targeting, suggesting disruption of HER2–AR signaling interactions. Conclusions: Findings demonstrate that HER2 blockade reduces HER2 expression in PC cells and alters AR nuclear abundance. These results provide evidence for crosstalk between HER2 and AR pathways in PC models and support the hypothesis that HER2 targeting impairs HER2-driven AR signaling dynamics.

Inhibiting α2,6-sialylation and its association with nectin-4 stability and macropinocytic uptake in bladder cancer.

792 Background: Enfortumab vedotin (EV), a Nectin-4–directed ADC, improves outcomes in advanced urothelial carcinoma; however, determinants of EV resistance remain unclear. Tumour cell surface sialylation and complex N-glycans are dysregulated in cancer and may modulate antigen abundance and ADC internalisation. To test whether α2,6-sialylation drives EV resistance by downregulating Nectin-4 and limiting macropinocytic uptake, and whether pharmacologic desialylation restores EV efficacy and potentiates EV–PD-1 combination therapy. Methods: We profiled sialylation/N-glycan states, Nectin-4 levels and EV sensitivity across bladder cancer (BCa) cell lines, patient-derived organoids and EV-resistant derivatives. Mechanistic studies included ST6GAL1 knockdown, ubiquitination/stability assays, FITC-EV tracking with endocytosis inhibitors, and FITC-dextran uptake. The sialyltransferase inhibitor P-3Fax-Neu5Ac was used to deplete α2,6-sialylation. In vivo efficacy was tested in subcutaneous models and in EV±anti-PD-1 ±P-3Fax-Neu5Ac settings. Immunogenic cell death (ICD) readouts included p-eIF2α, ATP release, HMGB1, and calreticulin exposure; T-cell phenotypes were analysed in tumour–PBMC co-culture and tumours. Statistics used t-tests/ANOVA with p < 0.05 considered significant. Results: High α2,6-sialylation/complex-type N-glycans correlated with low Nectin-4 and EV resistance, whereas high-mannose signatures associated with higher Nectin-4. Pharmacologic or genetic desialylation increased total and membranous Nectin-4 by reducing its ubiquitin-dependent degradation and restored EV sensitivity in vitro, including EV-resistant cells/organoids. EV internalisation in BCa cells occurred via macropinocytosis; α2,6-desialylation enhanced macropinocytic uptake and EV cytotoxicity. In mice, P-3Fax-Neu5Ac augmented EV antitumour activity and prolonged survival without added toxicity. Desialylation amplified EV-induced ICD and improved CD8^+ T-cell proliferation and function, thereby further potentiating EV+anti-PD-1 in vivo. Conclusions: α2,6-Sialylation is a tractable driver of EV resistance through Nectin-4 destabilisation and reduced macropinocytosis. Targeting sialylation reinstates antigen density, increases EV internalisation, heightens ICD, and strengthens EV±PD-1 efficacy. These data nominate tumour desialylation as a rational co-strategy to expand and deepen clinical benefit from EV in bladder cancer.

Physician perspectives on the implementability of a cardiovascular risk score for prostate cancer: A PRISM-guided evaluation.

57 Background: Cardiovascular disease (CVD) is the leading non-cancer cause of death among men with prostate cancer (PC), particularly during androgen-deprivation therapy. While CVD risk-prediction models are well established in the general population, barriers to integration within oncology workflows remain poorly defined. Guided by the PRISM and RE-AIM frameworks, this study evaluated multilevel determinants influencing adoption, feasibility, and sustainability of CVD risk-assessment tools in PC care. Methods: A national, cross-sectional survey of 45 physicians (medical oncology 49%, urology 38%, radiation oncology 13%) from 18 U.S. states was conducted. Respondents represented early- (27%), mid- (36%), and late-career (38%) clinicians across academic (87%) and community (13%) settings. Quantitative items mapped to PRISM/RE-AIM domains assessed adaptability, cost/resource feasibility, effectiveness, equity, and sustainability; open-ended responses explored contextual barriers and facilitators. Descriptive statistics summarized quantitative data. Results: Physicians reported moderate-to-high readiness to adopt a CVD risk-assessment tool, emphasizing workflow alignment and EHR integration over algorithmic complexity. Table 1 summarizes domain-specific findings. Ninety-three percent of respondents favored lab-independent models that minimize workflow disruption. Conclusions: Pre-implementation analysis highlighted that structural barriers, rather than algorithmic or statistical limitations, remain the primary obstacles to adopting CVD risk-assessment tools in prostate-cancer care. Physicians emphasized the need for EHR-integrated, non-laboratory-based, and time-efficient tools that align with routine oncology workflows and minimize cross-specialty friction. Addressing these practical and organizational determinants may be pivotal to achieving equitable, scalable, and sustainable cardio-oncology implementation across diverse practice settings. PRISM and RE-AIM constructs evaluation results. Construct Likely/Very Likely (%) Interpretation Perceived Effectiveness 87% Broad confidence in clinical utility Equity in Patient Reach 75% Strong perceived equity in reach Equity in Effectiveness 73% Expected to perform consistently across populations Adaptability to Workflow 71% High compatibility with existing clinic workflows Cost/Resource Feasibility 65% Feasible for resource-constrained settings Likelihood of Adoption 60% Moderate readiness for implementation Equity in Adoption 58% Equitable uptake possible despite resource differences Reach to Target Population 57% Moderate likelihood of reaching most patients Sustainability Over Time 51% Moderate long-term feasibility Consistency of Implementation 42% Need for standardized protocols