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Tailored Arylboronic Acid Derivatives Stabilize Perovskite Octahedron in Inverted Perovskite Solar Cells

ABSTRACT The absence of halide ions in perovskite at the buried interface remains a critical factor restricting the stability in efficient inverted perovskite solar cells (PSCs), mainly due to the metastable perovskite lattice. Herein, through a systematic investigation of the bonding mechanisms between arylboronic acid derivatives and perovskite, designing 5‐fluoro‐6‐hydroxypyridin‐3‐ylboronic acid (FO‐PyBA) anchors robustly on the perovskite surface vacancies to reinforce the perovskite octahedron to stabilize the buried interface. The –B(OH) 2 and C ═ O groups in FO‐PyBA promote the concurrent formation of C ═ O─Pb and B─O─Pb coordination bonds alongside N─H···I and O─H···I hydrogen bonds, which establish a robust coplanar multidentate anchoring with perovskite to reinforce the octahedral framework. Crucially, this more stable multidentate anchoring is enabled by precisely tailoring the interatomic distances of anchoring sites in derivatives to match the defect sites of perovskite. The FO‐PyBA effectively suppresses Pb/I vacancy defects and iodine ions migration to reduce interfacial nonradiative recombination. Consequently, it enabled inverted PSCs achieving a champion efficiency of 26.85% (certificated 26.70%) and maintained 94% of its initial efficiencies after 1000 h of operating under one‐sun illumination in N 2 .

Downregulation of ClC-3 chloride channels in dorsal root ganglia neurons contributes to bone metastasis-induced pain

Clinical implications of prostate specific antigen (PSA) flare and response dynamics in TALAPRO-2: A post-hoc analysis.

168 Background: In the phase 3 TALAPRO-2 study, talazoparib (TALA) + enzalutamide (ENZA) significantly improved radiographic progression-free survival (rPFS) and overall survival (OS) vs placebo (PBO) + ENZA as first-line treatment (tx) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) unselected (cohort 1) and selected for homologous recombination repair gene alterations (HRRm cohort). Here, we report post-hoc analyses of PSA kinetics from the final OS analysis cutoff date. Methods: Pts were randomized 1:1 to ENZA 160 mg + either TALA 0.5 mg or PBO once daily. The primary endpoint was rPFS; OS, a key secondary endpoint. We performed post hoc analyses of PSA flare (defined as a rise in PSA above baseline followed by a return to baseline or lower within 12 months), PSA response ≥50% (PSA50), PSA response ≥90% (PSA90), undetectable PSA (defined as PSA <0.2 ng/mL), and duration of PSA response. OS and rPFS were analyzed in PSA50 responders. Results: At data cutoff (Sep 3, 2024), PSA flare was observed in 2–3% of pts in both tx arms of the unselected and HRRm cohorts (Table). The median time for PSA to decline back to or below baseline after a rise above baseline was 57 days in both tx arms in the unselected cohort, and 60 and 117 days with TALA + ENZA and PBO + ENZA, respectively, in the HRRm cohort (Table). A greater proportion of pts taking TALA + ENZA achieved PSA50, PSA90, and undetectable PSA compared with PBO + ENZA in both cohorts (Table). In both cohorts, pts in the TALA + ENZA arm also had a longer median duration of PSA50 response, PSA90 response, and undetectable PSA vs PBO + ENZA (Table). In the unselected cohort, rPFS and OS directionally favored TALA + ENZA vs PBO + ENZA in PSA50 responders (rPFS HR: 0.72 [95% CI 0.57, 0.89], median 39.8 vs 27.6 months; OS HR: 0.90 [0.72, 1.13], median 53.3 vs 47.3 months). Similarly, in the HRRm cohort, rPFS and OS favored TALA + ENZA in PSA50 responders (rPFS HR: 0.51 [0.38, 0.70], median 36.1 vs 18.3 months; OS HR: 0.62 [0.44, 0.86], median not reached vs 38.2 months). Conclusions: In both cohorts, a greater proportion of pts in the TALA + ENZA arm achieved PSA responses with longer durations vs PBO + ENZA. Also, PSA flare was unusual (2–3%) and resolved in ~60 days (both cohorts) with TALA + ENZA vs ~60 days (unselected) and ~120 days (HRRm) with PBO + ENZA. In both cohorts, OS and rPFS numerically favored TALA + ENZA vs PBO + ENZA in PSA50 responders. Analyses of PSA responses for specific genes (e.g. BRCA2 ) are underway. Clinical trial information: NCT03395197 . Unselected Cohort HRRm Cohort TALA + ENZA (n=402) PBO + ENZA (n=403) TALA + ENZA (n=200) PBO + ENZA (n=199) PSA flare, n (%) 12 (3) 11 (3) 5 (2) 5 (3) Median time for PSA decline back to or below baseline, days 57 57 60 117 PSA50, n (%) 335 (83) 285 (71) 173 (86) 126 (63) Median duration, days 430 284 420 225 PSA90, n (%) 253 (63) 182 (45) 139 (70) 80 (40) Median duration, days 480 419 589 308 Undetectable PSA, n (%) 159 (40) 107 (27) 87 (44) 44 (22) Median duration, days 644 539 650 365

Impact of hospitalizations on health-related quality of life and overall survival in metastatic castration-sensitive prostate cancer: Insights from the ARANOTE trial.

53 Background: The impact of hospitalizations on health-related quality of life (HRQoL) and overall survival (OS) in metastatic castration-sensitive prostate cancer (mCSPC) has not been well characterized. Using data from the ARANOTE trial, we evaluated whether hospitalizations which occurred within 60 days prior to outcome data collection – either before or during participation in the trial - have an impact on HRQoL and OS. Methods: HRQoL was assessed using the Functional Assessment of Cancer Therapy–Prostate (FACT-P) instrument. FACT-P total scores from all available study visits were modeled longitudinally with generalized estimating equations. Covariates included number of prior all-cause hospitalizations, hospitalizations due to treatment-related adverse events, baseline pain (<4 vs ≥4), baseline ECOG performance status (0–1 vs 2), fatigue (any grade adverse event during participation in the trial), baseline age, and baseline weight. OS was evaluated using time-varying Cox proportional hazards regression. Covariates for the OS model included treatment, treatment-emergent adverse events, and number of prior all-cause hospitalizations. Results: Both the number of previous hospitalizations (–4.26 points; 95% CI: –6.89 to –1.63; p<0.001) and hospitalization due to treatment-emergent adverse events (–6.14 points; 95% CI: –9.92 to –2.36; p<0.001) were significantly associated with lower FACT-P total scores. Baseline pain ≥4 was the strongest negative predictor of HRQoL (–16.09 points; 95% CI: –19.46 to –12.73; p<0.001). ECOG performance status of 2 at baseline (–6.19; 95% CI: –13.62 to 1.25; p=0.10) and fatigue (–2.32; 95% CI: –7.68 to 3.05; p=0.40) were associated with lower HRQoL but did not reach statistical significance. Age (0.09; 95% CI: –0.08 to 0.25; p=0.29) and baseline weight (0; 95% CI: –0.08 to 0.09; p=0.96) had minimal effects. In survival analyses, the number of prior hospitalizations was strongly associated with mortality with each additional hospitalization increasing the hazard of death by 52% (HR 1.52; 95% CI: 1.39–1.66; p<0.0001). Conclusions: Prior hospitalizations were a consistent determinant of both reduced HRQoL and shorter OS in men with mCSPC, while baseline pain was the strongest driver of HRQoL decline. A post hoc analysis from the ARANOTE trial (Shore et al. 2025), found that darolutamide was associated with lower rates of hospitalization compared to placebo. Taken together, these findings highlight that treatments that decrease hospitalization with favorable tolerability profiles, such as darolutamide, may help sustain quality of life and survival by minimizing hospitalization burden. Clinical trial information: NCT04736199 .

Treatment and outcomes among patients with metastatic castrate resistant prostate cancer with an AR gene alteration: Analysis from the Kaiser Permanente Northern California Healthcare System.

91 Background: Androgen gene alterations (mutAR) are a key mechanism of resistance in metastatic castrate-resistant prostate cancer (mCRPC) and are most frequently found after exposure to Novel Hormonal Agents (NHA). Optimal treatment for patients with mCRPC and androgen receptor mutations is evolving. Current NCCN guidelines recommend continued androgen deprivation therapy (ADT) in mCRPC, with sequential use of novel hormone agents (NHA), or non-NHA therapies such as taxane-based chemotherapy, PARP inhibitors, immunotherapy, and Lutetium 177–PSMA-617 for appropriately selected patients. We sought to evaluate the benefit of therapy in patients with mutAR in a real-world setting. Methods: Between November 2017 and July 2025, 2193 patients in the Kaiser Permanente Northern California (KPNC) health system with advanced prostate cancer had tumor specimens examined by next generation sequencing (NGS). Of these patients, we retrospectively identified 67 mCRPC patients with mutAR. Patient records were reviewed to determine baseline demographic characteristics, therapies for Castrate Sensitive Prostate Ca (CSPC), and mCRPC characterized as NHA and non-NHA therapies, progression free survival (PFS), and overall survival (OS). The primary outcome was PFS on 1st and 2nd therapy for CRPC. Secondary outcomes were OS and PFS for NHA based therapy compared to non-NHA based therapy. Results: Median age for the 67 patients with mCRPC and mutAR was 72.4 years (Range 44-93). Forty-seven (70%) were non-Hispanic white; 8 (12%) were African American; and 6 (9%) were Asian. AR amplification was the most frequent alteration (74.6%). AR H875 was the most frequent ligand-binding domain mutation (11.9%). TP53 (52.2%), PTEN (34.3%) and CCND1 (13.4%) were the most common co-mutated genes. Median PFS was 11 months for 1 st line therapy and 4.5 months for 2 nd line therapy following diagnosis of CRPC based on Prostate Cancer Working Group criteria. Among the 67 patients with mCRPC with mutAR, 51 patients received ADT plus NHA, and 16 patients received ADT plus non-NHA therapy in the 1 st line setting. Median PFS was 13 months for ADT plus NHA and 5 months for ADT plus non-NHA therapy. Median PFS in the 2 nd line setting was 5 months for ADT plus NHA and 4 months for ADT plus non-NHA therapy. Median OS for the cohort was 34 months (95% CI 23.8-49 months). Median OS was 43.4 months for patients with ADT plus NHA and 20.7 months for the patients with ADT plus non-NHA therapy. Conclusions: In this real-world study within KPNC, we found that AR amplification was the most common AR gene alteration. In the 1st line CRPC setting, PFS was longer for patients receiving NHA vs non-NHA therapies. Better therapies are needed for subsequent line therapy.

Circulating kidney injury marker-1 (KIM-1) in metastatic renal cell carcinoma with divergent histologies (RCCdh): Biomarker analysis of the CAN-I trial.

538 Background: The CAN-I trial was a multi-center single arm phase II trial that evaluated cabozantinib, nivolumab and ipilimumab for treatment of metastatic RCCdh (NCT04413123). Previous studies have shown that circulating KIM-1 is associated with prognosis in clear cell RCC and that changes in KIM-1 are associated with treatment response. Preclinical data has shown that KIM-1 is overexpressed in most RCCdh except those that have a non-proximal tubular cell of origin, such as chromophobe RCC. We evaluated whether KIM-1 is associated with histology and outcomes in RCCdh. Methods: Patients with RCCdh were treated with cabozantinib, nivolumab and ipilimumab as previously described. Plasma KIM-1 was evaluated at baseline and cycle 3 day 1 (C3D1) using an established enzyme based electrochemiluminescence assay. Cox proportional hazards models were used to evaluate the associations between KIM-1 levels and outcomes. Results: Of 59 patients enrolled, 43 had plasma available for analysis. Median baseline KIM-1 was 3040 pg/mL (IQR: 842–8512) among patients with non-chromophobe RCC and 63 (IQR: 31–83) among patients with chromophobe RCC (Wilcoxon test, p < 0.0001). Higher KIM-1 at baseline was associated with worse IMDC risk score (Spearman rho = 0.37, p = 0.015). Among non-chromophobe RCC patients with paired samples (n=28), KIM-1 at C3D1 was significantly lower compared to baseline (median: 2900 vs 1232 pg/mL, Wilcoxon paired test, p = 0.002) and was strongly prognostic for PFS and OS after adjustment for IMDC risk and histology (Table). The 12-month OS rate from C3D1 was 83% among non-chromophobe patients who had decreasing KIM-1, and 37% among patients who had increasing KIM-1. Conclusions: Among patients with RCCdh, KIM-1 was overexpressed in papillary, translocation, and unclassified RCC compared to chromophobe RCC. Among non-chromophobe RCCdh patients, circulating KIM-1 is a potentially useful dynamic biomarker and should be further evaluated in trials. Circulating KIM-1 and association with outcomes. Baseline KIM-1 C3D1 KIM-1*** Hazard Ratio*(95% CI) P-value Hazard Ratio*(95% CI) P-value Unadjusted (PFS) 1.26 (0.97, 1.65) 0.088 1.53 (1.18, 1.98) 0.001 Adjusted (PFS)** 1.29 (0.94, 1.79) 0.118 1.55 (1.16, 2.07) 0.003 Unadjusted (OS) 1.23 (0.88, 1.70) 0.223 1.58 (1.20, 2.08) 0.001 Adjusted (OS)** 1.19 (0.79, 1.78) 0.413 1.66 (1.17, 2.34) 0.004 *Per unit log increase; **Adjusted for IMDC risk score and histology type (papillary vs other); ***Landmark analysis from C3D1.

Advancing the Landscape of RNAi Nanotherapeutics for Ischemic Heart Disease

ABSTRACT Ischemic heart disease (IHD) remains the foremost cause of mortality worldwide, characterized by extensive myocardial injury following infarction with limited regenerative capacity of the adult mammalian heart. RNA interference (RNAi) nanotechnology is revolutionizing cardiac therapy by leveraging the sequence‐oriented gene regulation that can overcome the obstacles hindering conventional therapeutic approaches. Here, we outline the evolving landscape of RNAi nanomedicine for cardiac repair, with an emphasis on therapeutic advances in myocardial infarction and atherosclerosis. We further discuss design considerations for constructing effective nanosystems, underscoring the critical principles by bridging mechanistic insights with material engineering. Finally, we delineate the translational pathway from bench to bedside, detailing current challenges and highlighting prospective opportunities for advancing RNAi therapeutics in cardiovascular therapy.

Structural basis of DNA aptamer A58 targeting the N-terminal domain of sarbecoviruses nucleocapsid protein

Cardiometabolic health’s influence on outcomes in men with localized high-risk prostate cancer (HRPCa) treated with pre-operative ADT ± AR pathway inhibition (ARPI).

225 Background: Cardiometabolic health (CMH) has a complex and divergent association with clinical outcomes in men with prostate cancer (PCa), exemplified by the differential impact of metabolic agents like metformin across disease states (e.g., active surveillance vs. metastatic). Increased adiposity is linked to higher risks of recurrence and lethal disease in localized PCa but may also enhance response to androgen receptor pathway inhibition (ARPI) in metastatic castration-resistant PCa (mCRPC), suggesting the need to study adiposity and prostate cancer in a stage-specific manner. Here, we investigated how baseline and treatment-induced changes in adiposity and lipid metabolites relate to clinical outcomes in men with localized high-risk PCa (HRPCa) treated with pre-operative androgen deprivation therapy (ADT) ± ARPI. Methods: Men with localized HRPCa who received 3–6 months of pre-operative ADT ± ARPI across three investigator-initiated clinical trials were included if baseline L3 vertebral computed tomography (CT) imaging was available. Body composition was quantified using an AI-assisted segmentation tool on CT scans obtained before treatment and at radical prostatectomy (RP). Fasted plasma lipid metabolites were profiled at both time points via LC/MS. Pathologic response was defined as ≤T2N0 disease, and PSA progression-free survival (PFS) as the time from RP to PSA ≥0.2 ng/mL or initiation of adjuvant/salvage radiotherapy if PSA remained <0.2 ng/mL. Results: Among 104 men (median age 63 years, baseline PSA 12.7 ng/mL), 77% had Gleason grade group 4–5 and 45% had clinical T3–4 disease. At radical prostatectomy, lower visceral adipose tissue (VATi; p = 0.002) and subcutaneous adipose tissue (SATi; p = 0.004) were significantly associated with higher rates of pathologic response. Conversely, greater adiposity measures at the time of RP were associated with an increased hazard of PSA progression (VATi HR 1.09, p = 0.04; SATi HR 1.14, p = 0.03). Intrapatient decreases in lipid metabolites, particularly acylcarnitines (p < 0.01), ceramides (p = 0.001), and triacylglycerols (p = 0.03), were observed among pathologic responders compared with non-responders, suggesting favorable metabolic adaptation during therapy. Conclusions: In men with localized HRPCa, elevated adiposity and intrapatient lipid metabolite changes in select pathways were associated with inferior clinical outcomes following pre-operative ADT ± ARPI. These findings demonstrate that specific features of CMH exert multifaceted effects on prostate cancer outcomes and warrant further investigation into CMH as a modifiable factor in PCa management.

A phase 1/2, open-label, randomized, dose-finding and dose expansion study of gedatolisib in combination with darolutamide in metastatic castration-resistant prostate cancer (mCRPC).

TPS304 Background: Progression to mCRPC occurs in most patients (pts) treated with androgen receptor pathway inhibitors (ARPI) for advanced disease. Preclinical studies demonstrate that AR and PI3K-AKT-mTOR (PAM) pathways interact through reciprocal negative feedback, whereby inhibition of one pathway activates the other (Crumbaker et al. Cancers [Basel] 2017). Combination of a PAM inhibitor + ARPI may produce synergistic antitumor effects in mCRPC, including in pts with prior ARPI progression. Results of a randomized Phase (Ph) 2 trial showed improved median radiographic progression-free survival (rPFS) when samotolisib, a dual PI3K-mTOR inhibitor, was added to enzalutamide in pts with mCRPC that progressed on abiraterone (Sweeney et al. Clin Cancer Res 2022). Methods: This open-label, multicenter, Ph 1/2 study will evaluate the safety and efficacy of gedatolisib combined with darolutamide in mCRPC that has progressed on ARPI. Key inclusion criteria: men ≥ 18 years with progressive mCRPC on or after treatment with at least one next-generation ARPI (eg, abiraterone, enzalutamide, apalutamide, darolutamide); ECOG 0-1; measurable disease per RECIST 1.1/PCWG3. Key exclusion criteria: adenocarcinoma with a small cell component or with ≥10% neuroendocrine type cells; prior treatment with PI3K, AKT, or mTOR inhibitor; prior chemotherapy or radiopharmaceutical therapy for mCRPC; uncontrolled type 1/2 diabetes; or active brain or leptomeningeal metastases. In Ph 1, 38 pts will be randomized to one of two dose arms to evaluate dose limiting toxicities (DLTs). Gedatolisib will be administered once weekly for 3-weeks-on/1-week-off (intermittent): Arm 1 – 120 mg and Arm 2 – 180 mg, with darolutamide 600 mg orally administered twice daily. Upon completion of Arms 1 and 2, up to 3 additional dose escalation Arms and a Ph1b part were added to determine RP2D. New dose escalation arms use a non-randomized, 3+3 dose escalation design exploring gedatolisib intermittent Arm 3 (240 mg) and Arm 4 (300 mg), respectively plus darolutamide. An optional Arm 5 may subsequently explore weekly gedatolisib doses with darolutamide. The Phase 1b part will include up to 4 cohorts comparing up to 2 dose levels and schedules. In Ph 2, up to ~18 pts will be enrolled to achieve a total of ~30 pts at the RP2D and selected dosing schedule. Primary objectives for Ph1/1b are to assess the safety and tolerability of gedatolisib in combination with darolutamide, to compare the Bayesian-Optimal interval utility score between arms, and to determine the RP2D. Primary objectives for Ph 2 are to assess the antitumor activity of the combination as demonstrated by rPFS. This trial (NCT06190899) is currently open for enrollment across 13 sites in four countries: United States, Spain, France, and United Kingdom. Clinical trial information: NCT06190899 .

Trimodal therapy versus radical cystectomy in muscle-invasive bladder cancer: The overlooked influence of informative censoring—A systematic review and meta-analysis.

729 Background: Informative censoring (IC) is a statistical bias that occurs when dropout rates differ between study arms and the mechanism of dropout is not random but related to unmeasured or unaccounted-for factors. Comparative analyses of trimodal therapy (TMT) versus radical cystectomy (RC) in muscle-invasive bladder cancer (MIBC) have produced conflicting results, potentially reflecting such bias. We conducted a systematic review and meta-analysis to quantify the potential impact of informative censoring on reported oncological outcomes in studies comparing these two treatment modalities. Methods: A comprehensive literature search was performed to identify studies including patients with cT2–T4, any N, M0 MIBC treated with TMT or RC. Eligible studies were evaluated for the risk of informative censoring affecting oncological endpoints. Published Kaplan–Meier curves were digitally reconstructed to extract time-to-event data. The inverse Kaplan–Meier method and log-rank test were applied to detect evidence of IC. A simulation analysis was performed to estimate the minimum proportion of events among censored patients required to offset the potential bias introduced by IC. Results: Six studies encompassing 8,594 patients were included in the analysis; only four utilized propensity score matching. Censoring imbalances were detected in 10 of 12 reported outcomes, favoring RC in five cases and TMT in five. Overall, censoring patterns favored RC for overall survival (OS), metastasis-free survival, and disease-free survival (log-rank, all p < 0.01). These results remained consistent despite stratification by propensity score matching and neoadjuvant chemotherapy use. For OS, the minimum event proportion required to offset the influence of IC ranged from 16% to 33%. After adjustment for the potential presence of IC, RC retained a significant survival advantage over TMT (5-year OS: 42% vs. 30%; p < 0.001). Conclusions: Most retrospective studies comparing TMT and RC are at high risk of IC, which tends to bias results in favor of RC. RC was associated with superior oncological outcomes even after accounting for this bias. These findings underscore the methodological limitations of comparing TMT and RC in non-randomized settings and call into question the acceptance of TMT as an equivalent alternative to RC based on retrospective data alone.

Bladder cancer innervation: Does it affect prognosis?

855 Background: Numerous studies have lately demonstrated the potentially important role of autonomic nerves in tumorigenesis and cancer progression. The association between nerve fiber density and tumor histopathological characteristics and clinical outcome varies across different cancer types. Only scant information on urinary bladder carcinoma innervation are available in the present literature sources. Methods: We analyzed 76 randomly selected cases of urinary bladder transitional cell carcinoma samples acquired by cystoscopy. Diagnoses were made based on WHO 2018 criteria. For detection of nerve fibers and their subtypes, dual indirect immunofluorescence staining was performed using the following antibodies: mouse monoclonal antibody against PGP9.5 (common neuronal marker) and rabbit polyclonal antibodies against tyrosine hydroxylase (TH, sympathetic nerves), vesicular acetylcholine transporter (VAChT, parasympathetic nerves) and calcitonin gene-related peptide (CGRP, sensory nerves). The secondary fluorescent antibodies gave red and green fluorescence, respectively. Nerve fiber density was evaluated using fluorescence microscope with a 40x objective (1 mm 2 surface) and scored semiquantitatively as absent, low (random fibers), medium (one fiber in 1-3 fields), or high (several fibers in one field). Results: The highest innervation density was observed in normal or inflamed mucosa. There was a decreasing innervation density from low-grade noninvasive through high-grade noninvasive to high-grade invasive tumors, with only scant nerve fibers in the latter. In general, most of the fibers contained sympathetic nerve filaments, while parasympathetic nerves were found only rarely and sensory filaments were only scant in few specimens. Virtually no nerve fibers were identified in the papillary stroma of the tumors. Conclusions: The significance of innervation density in the biology of bladder carcinoma remains unclear. Our results indicate that decreased nerve density is related to unfavorable prognosis of the tumor.

High‐Throughput In Vivo Subcellular Analysis of Gold Nanoparticles for Tumor Mitochondrial Targeting

ABSTRACT Mitochondrial targeting is a powerful strategy for cancer precision therapy. This study presents a subcellular DNA barcoding system for high‐throughput in vivo screening of mitochondrial‐targeting gold nanoparticles (NPs). After validating the robustness of the barcode system with six PEG/TPP‑modified NPs in vitro, the materials library expands to 30 NP species differing in shape, size, and ligand. Their biodistributions are systematically evaluated across subcutaneous, orthotopic, and contralateral tumor models at organ, cell‐subtype, and mitochondrial levels. This multiplexed approach yields more than 1000 data points on in vivo nanoparticle uptake and targeting behaviors, while requiring 30‐fold fewer mice than conventional approaches. The data reveal a strong correlation between tumor accumulation and mitochondrial delivery, indicating that effective tumor accumulation is a prerequisite for mitochondrial targeting. 80 nm cube (CL‑FA) and sphere (PL‑FA) nanoparticles tagged with folic acid (FA) emerge as top performers, with CL‑FA achieving 99% tumor regression when combined with mild photothermal therapy and mitochondria‐targeted siRNA delivery. Underlying mechanisms are attributed to geometry‐dependent protein corona formation patterns and cellular uptake via clathrin‑mediated endocytosis and specific curvature‑sensing protein interactions. Overall, this subcellular high‐throughput barcoding platform offers a rational framework to select inorganic nanomaterials for precision subcellular drug delivery.

Asymmetric Self‐Assembled Molecule With High Dipole Moment for Efficient Wide‐Bandgap Perovskite Solar Cells and Tandems

ABSTRACT Self‐assembled monolayers (SAMs) have shown considerable promise as hole‐transport layers (HTLs) in wide‐bandgap (WBG) perovskite solar cells (PSCs) and tandems. However, conventional SAM materials often face limitations such as substantial energy‐level misalignment and inefficient charge transport, which limit device performance. Here, we designed a carbazole‐based SAM molecule, 4‐(8‐bromo‐11H‐benzo[a]carbazol‐11‐yl) butyl) phosphonic acid (Br‐4PhCz), through a combined strategy of asymmetric π‐extension and terminal bromine substitution. The resulting Br‐4PhCz exhibits a large dipole moment, adopts a face‐on molecular orientation with uniform substrate coverage, and demonstrates superior self‐assembly quality. As a SAM‐based HTL, it enables the deposition of high‐quality WBG perovskite films over large areas, reinforces a robust buried interface, minimizes energy‐level misalignment, suppresses interfacial non‐radiative recombination, and enhances hole extraction. By integrating Br‐4PhCz, we obtained an impressive open‐circuit voltage of 1.36 V in WBG PSCs with a bandgap of 1.77 eV. Using these high‐performance WBG subcells, we fabricated all‐perovskite tandem devices that deliver maximum power conversion efficiencies of 29.35% (certified 28.98%) on 0.05 cm 2 and 28.83% (certified 28.49%) on 1 cm 2 devices.

Cell entry mechanisms of porcine enteric coronaviruses

Nezastomig (anti-PSMA×CD28) with or without cemiplimab (anti–PD-1) in patients with metastatic castration-resistant prostate cancer (mCRPC) or metastatic clear cell renal cell carcinoma (mccRCC): A phase 1/2 study.

TPS296 Background: Advanced mCRPC and mccRCC are urologic malignancies associated with poor prognoses, presenting an unmet need for novel therapies that can improve long-term outcomes for patients. Prostate-specific membrane antigen (PSMA) is a transmembrane protein with enzymatic activity and is highly expressed by prostate cancer cells and mccRCC neovasculature. PSMA has been validated as a therapeutic target for prostate cancer. Nezastomig (REGN5678) is a first-in-class, PSMA×CD28 co-stimulatory bispecific antibody (bsAb) that facilitates T-cell–mediated tumor killing by bridging PSMA-expressing cells with the costimulatory receptor CD28 expressed on T cells. Cemiplimab is an anti–programmed cell death-1 (PD-1) monoclonal antibody that targets inhibitory T-cell immune checkpoints. Preliminary results from the dose escalation phase of this study (NCT03972657) showed that nezastomig + cemiplimab reduced prostate-specific antigen (PSA) levels and induced radiographic responses; this provided the first evidence of clinical activity with a PSMA×CD28 co-stimulatory bsAb in solid tumors. Additionally, there was suggested correlation between clinical activity and high-grade immune-mediated adverse reactions in patients with mCRPC. The study has now been amended to reintroduce patient cohorts that will receive nezastomig + cemiplimab combination therapy following a benefit–risk evaluation. Methods: During the dose escalation phase of this open-label, Phase 1/2, first-in-human, multicenter study, nezastomig will be administered at increasing dose levels in combination with cemiplimab in separate cohorts for patients with mCRPC or mccRCC. When a maximum tolerated dose/presumptive recommended Phase 2 dose is identified, additional expansion cohorts may be evaluated. Patients with mCRPC must have received ≥2 prior lines of systemic therapy approved for metastatic or castration-resistant disease, including a second-generation androgen-receptor signaling inhibitor and a lutetium-based PSMA-targeted radioligand. Patients with mccRCC must have received ≥1 prior line of systemic therapy approved in the metastatic setting, including anti–PD-1/anti–PD-ligand 1 therapy and either ipilimumab or a tyrosine kinase inhibitor. Dose escalation primary endpoints are safety, tolerability, and nezastomig pharmacokinetics. The dose expansion primary endpoint is a composite response rate of PSA and radiographic responses per modified Prostate Cancer Working Group 3 criteria (mCRPC cohorts) and objective response rate per the Response Evaluation Criteria in Solid Tumors version 1.1 (mccRCC cohorts). This study is open and currently enrolling patients. Clinical trial information: NCT03972657 .

The practice of active surveillance for prostate cancer: Trends, variation, and quality within a large national health system.

347 Background: Active surveillance (AS) is broadly endorsed as preferred management for low-grade prostate cancer, but few data exist regarding variation and potential disparity in the use of AS interventions. This study characterizes the practice of AS broadly and deeply in the national VA Health Care System (VAHCS) in order to evaluate the adoption of AS for veterans with low and favorable intermediate risk prostate cancer. Methods: Pathology reports for biopsies, radiology reports for MRIs, and clinical and demographic data were collected from the VA Corporate Data Warehouse (CDW) for patients listed in the VA Informatics and Computing Infrastructure (VINCI) Prostate Data Core. The cohort includes patients with Gleason Grade Group (GG) 1 prostate cancer or GG 2 prostate cancer with less than 50% positive cores at diagnostic biopsy (DBx), as determined from pathology reports using natural language processing (NLP). Patients were stratified by whether they received treatment (radiation, prostatectomy, and/or orchiectomy/ADT) during the first 15 months or remained on AS or watchful waiting (WW). Patients with at least one PSA > 1 ng/mL or a confirmatory biopsy (CBx) prior to treatment were classified as managed with AS/WW. Patients were censored due to death, progression to metastatic status, no recorded PSA labs within 15 months, or a reported PSA value < 1 ng/mL. Results: In total, there were 173,725 patients with a positive biopsy for prostate cancer between 2005 and 2024. Of these patients, 79,053 were diagnosed with GG 1 or GG 2 prostate cancer with less than 50% positive cores and were either managed with AS/WW or received treatment during the first 15 months after diagnosis. For GG 1 patients, the proportion on AS increased from 32% in 2005 to 92% in 2024, with an increase from 15% to 52% for patients diagnosed with GG 2 cancer. Treatment patterns varied across VA facilities, with the proportion treated through AS/WW ranging from 35%-100% for GG 1 and 8-88% for GG 2. Only 28% of AS patients received CBx within 15 months of diagnosis, with this rate peaking between 2012 and 2015. From 2015 to 2025, MRI-guided biopsy increased from 1% to 31% for DBx and from 5% to 36% for CBx. Conclusions: AS has become the primary disease management approach for low and favorable intermediate risk prostate cancer within the VAHCS. MRI-guided biopsy is a more recent phenomenon, with a constant increase in the number of patients receiving an MRI within the year prior to biopsy. These findings suggest the need for further research to compare quality of AS across facilities and examine outcomes of AS.

FORAGER-2: A randomized phase 3 study evaluating the efficacy and safety of vepugratinib combined with enfortumab vedotin and pembrolizumab in untreated locally advanced or metastatic urothelial carcinoma with an FGFR3 genetic alteration.

TPS895 Background: Treatment with enfortumab vedotin (EV)/pembrolizumab (P) has significantly improved clinical outcomes for untreated locally advanced or metastatic urothelial cancers (LA/mUCs). However, with a median progression-free survival (PFS) of only ~12 months, most patients (pts) will still progress and succumb to their disease. Activating alterations in fibroblast growth factor receptor 3 (FGFR3) occur in 15-20% mUC. Vepugratinib is an oral, highly potent, isoform-selective FGFR3 inhibitor, designed to limit off-target toxicity associated with pan FGFR inhibitors. The FORAGER-1 phase 1 study (NCT05614739) demonstrated promising efficacy in pts with previously treated FGFR3-altered mUC (Drakaki, ESMO 2025). The favorable safety profile observed at the selected monotherapy dose, 200 mg BID, supports combining vepugratinib with other agents. Preclinical studies in FGFR3-altered mUC demonstrate vepugratinib induces upregulation of cell-surface NECTIN-4 and enhanced antitumor activity when given in combination with EV/P (Goetz, AACR-NCI-EORTC, 2025), providing a strong biological rationale for combination with EV/P. FORAGER-2 (NCT07218380) is a randomized, double-blind, placebo-controlled phase 3 study evaluating the addition of vepugratinib to EV/P in pts with previously untreated LA/mUC harboring an FGFR3 genetic alteration. Methods: Approximately 450 pts with untreated, histologically confirmed LA/mUC with an activating FGFR3 mutation or fusion determined via local molecular testing (tissue or blood), will be randomized in a 1:1 ratio to receive EV/P + vepugratinib or EV/P + placebo. Pts may receive 1 cycle of standard of care EV/P before study enrollment for cases where immediate treatment is clinically indicated while awaiting FGFR3 test results. Treatment will continue until radiographic progression or unacceptable toxicity. Pts will be stratified at baseline by Eastern Cooperative Oncology Group performance status score, presence of liver or bone metastases, and geographical region. The primary endpoint is PFS assessed by blinded independent central review. Key secondary endpoints include overall survival, investigator-assessed PFS, objective response rate, duration of response, PFS2, safety, and patient-reported outcomes such as health-related quality of life. The randomized portion of FORAGER-2 will be preceded by a single-arm safety lead-in. Enrollment is ongoing and will be opened in approximately 19 countries. Clinical trial information: NCT07218380 .

Genomic analyses of bilateral testicular germ cell cancers (BITCOIN study) from the Italian Germ Cell Cancer Group (IGG).

617 Background: Despite Testicular Germ Cell Tumors (TGCT) being the most common malignancy in young men aged 15 to 44 years, bilateral TGCT (bTGCT) accounts for 2–5% of TGCT cases. To date there are only small case reports exploring genomic aberrations in bTGCT, with no shared single nucleotide variants or structural chromosomal rearrangements identified in paired TGCTs, suggesting they develop independently. Methods: BITCOIN is an ambispective translational study that recruited 53 patients with bTGCT within 6 Italian Canters of Reference for TGCTs. We collected FFPE tissue specimens of both tumors (29 pts), or from one of those (14 pts) along with a blood sample when feasible (43 pts). Illumina Stranded Total RNA sequencing was performed to generate 100 bp-paired reads that were aligned to hg38 human genome using HISAT2. Raw gene-level counts, obtained with FeatureCounts algorithm, were then filtered for low expression, and normalized using TMM method for downstream differential expression analysis (DGE) via edgeR. Visualization of differentially expressed genes (FDR < 0.05 and logFC > 1.5) and gene set enrichment (GSE) analysis were carried out with ggplot2 and clusterProfiler, respectively. Results: Overall, in this preliminary analysis, 57 samples were sequenced from 30 unique pts. Of these, 27/57 (47%, representing 19 unique pts) reached at least 30 million reads and >50% of reads assigned to features. Notably, mean age of these specimens was 8 years. We identified among the bTGCT most expressed genes, embryonic/stem-like TGCT signatures (i.e. NR6A1 and BCN2 ) together with epigenetic regulators ( KMT2C, ARID1B ) and lncRNA drivers ( MALAT1 , NEAT1 , FTX , XACT ). DGE analysis was performed on 8 pts with paired tumors and 11 pts for whom only one tumor sample was available, highlighting differentially expressed genes according to the site (right [R] vs left [L]). Among these, APOB was the main marker of L localization. Finally, GSE using the Hallmark gene sets revealed a mild enrichment of epithelial-mesenchymal transition and TNFA signaling via NFKB (NES > 0.5 and FDR < 0.01 for both) in the L side. Conclusions: To date this represents the largest study on bTGCT. In this preliminary analysis, we demonstrate the feasibility of RNAseq on archival FFPE tissues identifying possible genomic characteristics of bilateral cancers.

Ion Mobility Engineering for Balanced Impedance Matching and Electromagnetic Loss

ABSTRACT Suppressing ionic motion in ionogels for the fabrication of unprecedented EMW absorbers remains an unexplored frontier, as researchers have predominantly focused on facilitating rather than inhibiting ion transport. Herein, a rational double‐network design strategy is developed to synthesize an ion motion‐suppressed ionogel with record‐high EMW absorption performance (minimum reflection loss −63.45 dB and 6.19 GHz bandwidth) that surpasses most ionogel absorbers. The double‐network is constructed via the entangled assembly of polymethyl methacrylate and poly(2‐acrylamido‐2‐methyl‐1‐propanesulfonic acid) (PAMPS) in 1‐ethyl‐3‐methylimidazolium methanesulfonate ionic liquids. Thanks to strong electrostatic interactions, ion motion is restrained by the PAMPS network, balancing impedance matching and dielectric loss under EM fields. The resultant ionogels demonstrate a minimum reflection loss of ‐63.45 dB at 1.8 mm and a broad effective absorption bandwidth of 6.19 GHz (fully covering the Ku‐band), both setting up new EMW absorption benchmarks among ionogels and their hybrids. Unlike emerging approaches that promote ionic conduction for loss, here we suppress ion mobility to optimize impedance matching, a paradigm shift in ionogel design. In essence, this work introduces a strategy to design high‐performance, multifunctional ionogels, paving the way for next‐generation flexible EMW absorbers in 5G/6G communications and wearable electronics.